Indium trichloride-catalyzed conjugate addition of amines to α,β-ethylenic compounds in water

Article abstract of DOI:10.1055/s-1998-1845

Catalytic amount of indium (III) trichloride efficiently catalyzed Michael reaction between amines and α,β-ethylenic compounds in water and under mild conditions. Indium trichloride can be recovered and reused without decrease in yield.

Full text of DOI:10.1055/s-1998-1845

September 1998
SYNLETT
975
Indium Trichloride-Catalyzed Conjugate Addition of Amines to α,β-Ethylenic Compounds in
Water
Teck-Peng Loh,* and Lin-Li Wei
Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
Received 29 May 1998
Abstract: Catalytic amount of indium (III) trichloride efficiently
catalyzed Michael reaction between amines and α,β-ethylenic
compounds in water and under mild conditions. Indium trichloride can
be recovered and reused without decrease in yield.
One of the most straightforward routes for the synthesis of β-amino
1
derivatives such as β-aminoesters is via the Lewis acid-mediated
addition of amines to α,β-ethylenic compounds. However, only simple
primary nonbulky amines can react with simple unsubstituted acrylic
2
,3
4
compounds without special activation such as high temperature, high
5
6
pressure, the use of appropriate catalysts, as well as with various such
combinations. In order to develop new catalysts to promote this
7
reaction under mild reaction conditions, we examined a novel and useful
catalyst namely indium (III) trichloride.
Organic reactions in water or aqueous media have recently attracted
8
,9
great interest. Recently, we have reported indium trichloride as an
1
0-12
excellent catalyst in the Mukaiyama aldol reactions,
Diels-Alder
reactions, aldol-type Mannich reaction and Michael reaction15 neat
or in water under mild conditions. As indium trichloride has these
unique properties compared to other Lewis acids which include stability
and recoverability from water, we are interested to apply it to other
carbon-carbon bond formation reactions in water. In this paper, we
showed that indium trichloride can promote the conjugate addition of
α,β-ethylenic substrates such as acrylate, crotonate and acrylnitrile with
primary and secondary amines in water (Scheme 1).
13
14
Scheme 1
A typical experimental procedure is as follows: An α,β-ethylenic
substrate (1 mmol) and InCl (20 mol%) were stirred in distilled water
3
(5 mL) at room temperature for 10 minutes. Amine (1.2 equiv.) was then
added in small portions. The resulting mixture was stirred for 6-40 hours
at room temperature. Usual workup afforded the β-amino products. The
results are summarized in Tables 1, 2 and 3.
Indium trichloride was first tested for its effectiveness as a Lewis acid in
the reaction of methyl acrylate and benzylamine in water (Table 1,
entries 1 and 2). Competitive experiments were carried out with and
without InCl3 in water. The reaction of methyl acrylate with
benzylamine in the presence of InCl3 was completed in 6 h giving a
mixture of mono and disubstituted products (70 %). However, the
control reaction without any catalyst gave much lower yields (20 %)
confirming the effectiveness of InCl3 as catalyst for the addition of
amine to α,β-unsaturated ester. Similarly, when the reaction of
acrylnitrile with diisopropyl amine was carried out in the presence of
InCl3 (Table 1, entries 3 and 4), the monosubstituted product was
obtained as the sole product in much higher yield as compared to the
benzylamine to trans-ethyl crotonate and trans-ethyl 4,4,4-trifluoro-
crotonate afforded the corresponding products in higher yield than the
control reactions without InCl separately (Table 1, entries 5 to 8). These
3
results confirmed the efficiency of InCl as a catalyst for the conjugate
3
addition of amines to α,β-ethylenic compounds and show that recovered
InCl can be reused without decrease in yield.
3
reaction without InCl . InCl can also be recovered and reused. The
3
3
yields of the 2nd and 3rd runs were comparable to the first run (Table 1,
entry 3). Finally, the InCl -catalyzed addition of (R)-methyl
After confirming the efficiency of indium trichloride, a wide variety of
primary and secondary amines were reacted with acrylate and
3

9
76
LETTERS
SYNLETT
acrylnitrile in water. The results are summarized in Tables 2 and 3. The
following characteristic features of these reactions are noted: (1) In all
cases indium trichloride catalyzed the addition of various amines with
acrylate and acrylnitrile in water gave the corresponding β-amino esters
in moderate to high yields. (2) InCl3 can catalyze both alkyl and
aromatic amines addition reactions. For the reactions of simple alkyl
amines such as dimethylamine, the yields are high. (3) Reactivities of
nonbulky amines relate to their basicity (Tables 2 and 3, entries 1, 2 and
In conclusion, InCl3 is an efficient catalyst for Michael conjugate
addition of amines to α,β-unsaturated ethylenic compounds in water
under mild reaction conditions.
We acknowledge the financial support for this project from the National
University of Singapore (Grant RP 940633, RP 950609, RP 970615 and
RP 970616).
References and Notes:
3). Generally, higher basicity results in higher yields. (4) The additional
(1) Ben Ayed, T.; Amiri, H.; El Gaied M. M.; Villieras J. Tetrahedron
alkylation reaction is difficult to control (Table 2, entries 5, 6 and 7;
Table 3, entries 7 and 8). This further alkylation cannot be avoided
either by changing the addition sequence or the changing of the ratios of
1
995, 35, 9633 and references cited therein.
(2) Pfau, M. Bull. Soc. Chim. France 1967, 117.
reactants. (5) InCl can be recovered and reused after the completion of
3
(3) Perlmutter, P. Conjugate Addition Reaction in Organic Synthesis;
reactions without any decrease in yields (Table 1, entries 3). The
experimental procedure is very simple: after being extracted with ethyl
acetate three times, the aqueous layer was separated and reused directly
for the second run.
Pergamon Press: Oxford, 1992.
(
4) Furukawa M, Okawara T, Terawaki Y. Chem. Pharm. Bull. 1977,
5, 1319.
2
(
(
(
5) D'Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112.
6) Matsubara, S.; Yoshioka, M.; Utimoto, K. Chem. Lett. 1994, 827.
7) Jenner, G. Tetrahedron Lett. 1995, 36, 233.
Preliminary studies using chiral amine ((R)-methyl benzylamine) with
trans-ethyl crotonate resulted in poor diastereoselectivity as shown
below (Scheme 2). The isomers resulting from trans-ethyl crotonate can
be easily separated by silica gel chromatography. Interestingly, indium
trichloride can also catalyze the addition of (R)-methyl benzylamine to
trans-ethyl 4,4,4-trifluorocrotonate to afford the corresponding chiral
trifluoromethylated amine in good yield. This method provides an easy
entry to trifluoromethylated amine which is otherwise difficult to obtain.
We have also studied the reaction of ethyl (S)-(+)-3-(2,2-dimethyl-1,3-
dioxolan-4-yl)-cis-2-propenoate with benzylamine as shown in Scheme
(8) Lubineau, A.; Ange, J.; Queneau, Y. Synthesis 1994, 741.
(
9) Li, C.-J. Chem. Rev. 1993, 93, 2023.
(
10) Loh, T.-P.; Pei, J.; Cao, G.-Q. J. Chem. Soc., Chem. Commun.
1
996, 1819.
(
(
(
11) Loh, T.-P.; Pei, J.; Koh, S.-V.; Cao, G.-Q.; Li, X.-R. Tetrahedron
Lett. 1997, 38, 3465.
12) Loh, T.-P.; Chua, G.-L.; Vittal, J. J.; Wong, M.-W. J. Chem. Soc.,
Chem. Commun. 1998, 861.
3
. Efforts to increase the diastereomeric selectivity using other chiral
amines are ongoing.
13) Loh, T.-P.; Pei, J.; Lin; M. J. Chem. Soc., Chem. Commun. 1996,
2
315.
(
(
(
14) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
15) Loh, T.-P.; Wei, L.-L. Tetrahedron 1998, 54, 7615.
16) Kinas, R.; Pankiewicz, K.; Stec, J. W.; Farmer, B. P.; Foster, B. A.;
Jarman, M. J. Org. Chem. 1977, 42, 1650.
(
(
(
17) The diastereomeric ratio was determined by 19F NMR and the
Scheme 2
absolute stereochemistry of the products was not determined.
18) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.; Yamada, Y.
Tetrahedron Lett. 1983, 24, 3009.
19) The ratio of cis/trans of recovered ethyl (S)-(+)-3-(2,2-dimethyl-
1
,3-dioxolan-4-yl)-2-propenoate is 5/95 respectively as compared
to the pure cis starting material.
Scheme 3