InCl3-catalyzed three-component asymmetric Mannich-type reaction in methanol

Article abstract of DOI:10.1021/ol0265968

(graph presented) A one-pot InCl₃-catalyzed Mannich-type reaction was carried out in methanol. High diastereoselectivities and high yields were obtained. In addition, after the reaction was completed, InCl₃ can be recycled and reused without a drop of activity and selectivity.

Full text of DOI:10.1021/ol0265968

ORGANIC
LETTERS
2
002
Vol. 4, No. 21
647-3650
InCl -Catalyzed Three-Component
Asymmetric Mannich-Type Reaction in
Methanol
3
3
Teck-Peng Loh* and Shui-Ling Chen
Department of Chemistry, National UniVersity of Singapore,
3
Science DriVe 3, Singapore 117543
chmlohtp@nus.edu.sg
Received July 23, 2002
ABSTRACT
A one-pot InCl
addition, after the reaction was completed, InCl
3
-catalyzed Mannich-type reaction was carried out in methanol. High diastereoselectivities and high yields were obtained. In
can be recycled and reused without a drop of activity and selectivity.
3
The Mannich reaction is one of the most important funda-
mental reactions in organic chemistry because it affords
synthetically and biologically important â-amino carbonyl
compounds. Therefore, it has found wide applications in
the syntheses of numerous pharmaceuticals and natural
products.
Scheme 1. Three-component Mannich-Type Reaction with
InCl in Water
3
1
,2
Most recently, our group has reported a novel three-
3
component coupling InCl -catalyzed Mannich-type reaction
in water (Scheme 1).3 It has been found that the Mannich-
type reaction involving aldehydes, amines, and silyl enol
ethers/ketene silyl acetals proceeds smoothly in water under
,4
to the addition of nonenolizable aldehydes and aromatic
amines. Furthermore, efforts to develop an enantioselective
Mannich-type reaction in water by using a chiral amine were
unsuccessful. In this paper, we present a new approach to
overcome these limitations by using MeOH as solvent.
Recently, Vilaivan and co-workers have reported an
indium-mediated Barbier-type allylation of unactivated al-
the catalysis of InCl
3
to afford the â-amino carbonyl
compounds in high yields. However, this method was limited
(1) For comprehensive reviews: (a) Risch, N.; Arend, M.; Westermann,
B. Angew. Chem., Int. Ed. 1998, 37, 1044 and references therein. (b)
Tramontini, M.; Angiolini, L. In Mannich Bases, Chemistry and Uses;
CRC: Boca Raton, FL, 1994, and references therein. (c) Volkmann, R. A.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 1, p 355 and references therein.
5
dimines with allyl bromides in alcoholic solvents. The ability
of this reaction to work with a wide variety of substrates
has encouraged us to investigate the asymmetric Mannich-
type reaction in methanol using InCl3.
First, we screened various chiral amines such as (R)-
phenylethylamine, (R)-1-naphthylethylamine, (R)-2-naph-
(2) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blacky Academic
and Professional: London, UK, 1998. (b) Li, C. J. Chem. ReV. 1993, 93,
2
1
1
3
023. (c) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002,
24, 5640-5641. (d) Akiyama, T.; Onuma, Y. J. Chem. Soc., Perkin Trans.
2002, 1157-1158. (e) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002,
5, 209-217.
(
3) Loh, T. P.; Wei, L. L. Tetrahedron Lett. 1998, 39, 323-326.
(4) Loh, T. P.; Liung, S. B. K. W.; Tan, K. L.; Wei, L. L. Tetrahedron
(5) Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y. Tetrahedron
Lett. 2001, 42, 9073-9076.
2
000, 37, 3227-3237.
1
0.1021/ol0265968 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002

Table 1. Diastereoselective Mannich-Type Reaction of Chiral
Table 2. Diastereoselective Mannich-Type Reaction with
Amines, Benzaldehyde, and
L-Valine Methyl Ester as the Chiral Auxiliary
1
-Methoxy-2-methyl-1-trimethylsilyloxypropene
a
b
1
Isolated yield. The diastereomeric ratio was determined by H and
13
c
8
C NMR. .Absolute configuration assigned by analogy.
thylethylamine, L-phenylglycine methyl ester, and L-valine
methyl ester to test the reaction as well as the diastereo-
selectivity. Table 1 summarizes the results obtained with
various chiral amines, benzaldehyde, the commercially
a
Isolated yield. b The diastereomeric ratio was determined by H and
1
13
c
8
C
N
M
R
.
A
b
s
o
l
u
t
e
c
o
n
f
i
g
u
r
a
t
i
o
n
a
s
s
i
g
n
e
d
b
y
a
n
a
l
o
g
y
.
6
available 1-methoxy-2-methyl-1-trimethylsilyloxypropene,
The excellent diastereoselectivities observed may then be
explained by using the transition state model as shown in
Figure 1. In this model, InCl , nitrogen, and the carbonyl
7
and 20 mol % of InCl
3
.
3
In all cases, the desired â-amino esters were obtained in
excellent yields. The highest diastereomeric excess was
obtained when L-valine methyl ester was used as a chiral
source (entry 5) while L-phenylglycine gave low selectivity
(entry 4). Therefore, L-valine methyl ester was used as a
chiral amine in subsequent reactions with various aldehydes.
The results are shown in Table 2.
As shown in Table 2, these reactions proceeded smoothly
in MeOH to afford the desired products in good yields with
moderate to excellent diastereoselectivities. Furthermore, this
protocol works with both aromatic and aliphatic aldehydes.
Most importantly, these reactions work with enolizable
aldehydes (entry 2 and 3), although the yields and selectivi-
ties were moderate. Entry 1 showed that these reactions could
also work with an aldehyde having a hydroxyl functional
group, however, with lower selectivity. As a result, no
protection of the hydroxy group is required. This low
selectivity may be attributed to the competing chelation
between the hydroxyl group and the ester functionality of
the chiral auxiliary.
Figure 1. Transition state model of the highly diastereoselective
Mannich-type reaction.
group of the ester are chelated together to form a rigid
bidentate conformation. The bulky isopropyl group of the
L-valine methyl ester selectively shields the Re face, thus
leaving the Si face available for attack, thereby rendering
the nucleophillic addition process a highly diastereoselective
one. As a result, the (R,S)-diastereomer is the major product
in all cases.
1
A H NMR study has been carried out to investigate the
(
6) The reaction was carried out with other nucleophiles, for example,
1-ethoxyvinyloxy)trimethylsilane gave the Mannich product in moderate
yields, but the silylenol ether did not give any desired product.
7) 5 and 10 mol % of InCl3 were used in the investigation respectively
and both gave equally good results.
(
3 3
progress of the reaction with and without InCl in CD OD
(
Figure 2). It was found that, with InCl , the reaction was
3
(
completed in 40 min after addition of the 1-methoxy-2-
3648
Org. Lett., Vol. 4, No. 21, 2002

Figure 2. 1H NMR study of the effect of InCl
methyl-1-trimethylsilyloxypropene. However, without InCl
3
3
in the Mannich-type reaction with CD OD.
3
,
even though a small amount of the imine was formed, there
was no reaction between the imine and 1-methoxy-2-methyl-
Table 3. Asymmetric Mannich-Type Reaction with Recycled
InCl
3
1-trimethylsilyloxypropene. All these evidences showed not
only that InCl is a driving force for imine formation but
3
also that it plays a very essential role in the nucleophilic
attack of the imine.
Since InCl plays an important role in our methodology,
3
we then turned our attention to recycling and reusing the
9
catalyst. To demonstrate the efficiency of the recovered
InCl
aldehydes, L-valine methyl ester, and 1-methoxy-2-methyl-
-trimethylsilyloxypropene in MeOH was carried out with
recycled InCl . The results are shown in Table 3. It was found
that by using recycled InCl , the selectivities and yields are
as good as with fresh InCl
3
, the three-component Mannich-type reaction of various
1
3
3
3
.
An attempt was made on removing the chiral auxiliary. It
was found that the ester group on the chiral auxiliary could
be selectively reduced with NaBH
4
in THF/MeOH (Scheme
a
Entry 2 and entry 3 are in order of sequence when the reaction was
2). This suggests that the chiral auxiliary can be further
b
carried out with recycled InCl3 from the previous reaction. Isolated yield.
10
removed by oxidative chiral auxiliary cleavage with H
5 6
IO .
c
1
13
d
The diastereomeric ratio was determined by H and C NMR. Absolute
configuration assigned by analogy.8
(8) Ojima, I.; Inaba, S. Tetrahedron Lett. 1980, 21, 2081-2084.
Org. Lett., Vol. 4, No. 21, 2002
3649

Acknowledgment. We would like to thank the National
University of Singapore for providing the research grants
and also the Chemical Process and Engineering Centre and
Singapore Millennium Fund for providing the scholarship.
Scheme 2. Selective Reduction of One Ester Functionality
from the Mannich Product with NaBH
4
Supporting Information Available: General procedure
of the three-component asymmetric Mannich reaction and
1
13
H and C NMR spectra of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0265968
3
In brief, we have reported a InCl -catalyzed asymmetric
three-component Mannich-type reaction using methanol. This
reaction works with both enolizable and nonenolizable
aldehydes, as well as with aliphatic amines. This new method
provides an easy entry into synthetically useful â-amino
carbonyl compounds in protic solvent.
(
9) First, the MeOH was removed azeotropically followed by the
extraction of the organic compounds with ether/hexane (1:1, ×5). The
remaining residue in the reaction flask was the recycled InCl3, which would
be ready for further reactions.
(
10) Alvara, G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7, 2083-
2092.
3650
Org. Lett., Vol. 4, No. 21, 2002