Asymmetric Mannich-type reactions catalyzed by indium(III) complexes in ionic liquids

Article abstract of DOI:10.1016/S0040-4039(03)00189-8

In(III) complexes efficiently catalyse asymmetric Mannich-type reactions in ionic liquids with high diastereoselectivity and good yield.

Full text of DOI:10.1016/S0040-4039(03)00189-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2405–2408
Asymmetric Mannich-type reactions catalyzed by indium(III)
complexes in ionic liquids
Shui-Ling Chen,a Shun-Jun Jib,* and Teck-Peng Loha,b,
*
aDepartment of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543
bCollege of Chemistry and Chemical Engineering, SooChow University, Jiangsu 215006, China
Received 18 November 2002; revised 7 January 2003; accepted 17 January 2003
Abstract—In(III) complexes efficiently catalyse asymmetric Mannich-type reactions in ionic liquids with high diastereoselectivity
and good yield. © 2003 Elsevier Science Ltd. All rights reserved.
The asymmetric synthesis of various functional
molecules is one of the most important tasks in modern
organic synthesis.1 Therefore, it is important to develop
efficient asymmetric CꢀC bond forming reactions. Fur-
thermore, there are increasing concerns about environ-
mental effects, which require synthetic manipulation
that minimize the use of hazardous chemicals. Aiming
to achieve this goal, many strategies have been devised
and investigated, especially by replacing the traditional
organic solvents with other non-toxic solvents such as
water or supercritical carbon dioxide. Recently, ionic
liquids2 have attracted extensive interest as excellent
alternatives to organic solvents, due to their favourable
properties, such as non-flammability, no measurable
vapour pressure, low toxicity, reusability, low cost and
high thermal stability. In addition to the polar proper-
ties of ionic liquids, they are non-coordinating, which
avoids any undesired solvent binding in pre-transition
states, and hence offer great advantages for asymmetric
synthesis. As a result, ionic liquids are considered as
promising alternative solvents for organic reactions.
Over the past few years, these liquids have generated a
significant amount of interest.3 However, stereochemi-
cal features in these solvents have not been studied in
detail. In this paper, we demonstrate an asymmetric
Mannich-type reaction in ionic liquids (Scheme 1).
Recently, an In(III) complex-catalyzed, three-compo-
nent Mannich-type reaction using aldehydes, amines
and silyl enol ethers/ketene silyl acetals in water has
been developed in this laboratory.4 Although high
yields were obtained, this protocol was mainly limited
to non-enolizable aldehydes and aromatic amines.
These limitations have hindered the development of an
asymmetric version of this reaction. As a result, we
directed our studies to investigate the reaction in ionic
liquids. From our previous experience, the results
obtained using
L
-valine methyl ester as a chiral auxil-
-valine methyl ester
iary were excellent.5 As a result,
L
was employed as a chiral auxiliary for the asymmetric
version of the In(III) complex-catalyzed Mannich-type
reaction.
Firstly, we investigated the effect of different ionic
liquids on the asymmetric Mannich-type reaction using
InCl3. Four different ionic liquids were used in our
investigation, i.e. butylmethylimidazolium tetra-
−
fluoroborate ([bmim][BF4 ]), hexylmethylimidazolium
Scheme 1. InCl3-catalyzed asymmetric Mannich-type reaction in ionic liquids.
Keywords: InCl3; catalyst; asymmetric Mannich-type reaction; ionic liquids.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00189-8

2406
S.-L. Chen et al. / Tetrahedron Letters 44 (2003) 2405–2408
−
−
tetrafluoroborate ([hmim][BF4 ]), octylmethylimida-
Next, a study was performed using [bmim][BF4 ] with
−
zolium tetrafluoroborate ([omim][BF4 ]) and octyl-
various aldehydes in the present of InCl3. The yields
and the diastereomeric ratios are shown in Table 2. In
all cases, L-valine methyl ester was found to be a good
methylimidazolium chloride ([omim][Cl−]). The results
are shown in Table 1.
chiral auxiliary for both aromatic and aliphatic alde-
hydes to afford the products in moderate to good yields
with high diastereoselectivities. Contrary to the reaction
carried out in water, even enolisable aldimines can be
used in this system.
It was found that this asymmetric Mannich-type reaction
proceeded smoothly in all three [BF4 type ionic liquids
−
but not in [omim][Cl−]. Interestingly, the yields of the
Mannich product 1 increased gradually when the cation
carbon chain length of the ionic liquid used was reduced.
Moreover, although the diastereoselectivities of the Man-
nich product 1 were consistently high, the ratios of the
Mannich product to the aldol side product varied. The
percentage of the Mannich product increased with
shorter cation carbon chain lengths. This interesting
result shows that we can progressively reduce the aldol
side product by just altering the ionic liquid.
All efforts to recycle and reuse the ionic liquids in the
same reaction failed to afford the desired Mannich
product. However, addition of a further 0.2 equiv. of
−
InCl3 to recycled [hmin]BF4 , allowed the asymmetric
Mannich-type reaction to proceed in 50% yield and
82% de with 4-chlorobenzaldehyde.
Table 1. Investigation of an asymmetric Mannich-type reaction using various ionic liquids
Ionic liquid
Yielda
Diastereomeric ratiob (R:S)
1:2
[omim][BF4−], n=7
[hmim][BF4−], n=5
[bmim][BF4−], n=3
[omim][Cl−], n=7
50%
65%
71%
92:8
93:7
93:7
73:27
93:7
95:5
No desired product
a Isolated yield of Mannich product 1.
b The diastereomeric ratio of 1 was determined using 1H and 13C NMR spectroscopy.
−
Table 2. InCl3-catalyzed asymmetric Mannich-type reaction with various aldehydes using [bmim][BF4
]

S.-L. Chen et al. / Tetrahedron Letters 44 (2003) 2405–2408
2407
In(OTf)3 can be recycled and reused and it was envis-
aged that this In(III) complex could be employed in the
three-component asymmetric Mannich-type reaction
with various aldehydes. The results are shown in Table
3. To our delight, In(OTf)3 also performed very well as
a catalyst in this reaction.
selectivity were comparable to that of fresh ionic liquid
and catalyst. However, the third cycle using benzalde-
hyde resulted in a decrease in yield to only 13% and the
selectivity was found to be only 76% de.
In summary, we have developed a highly asymmetric
Mannich-type reaction catalyzed by InCl3 or In(OTf)3
using ionic liquids. In general, the reactions proceeded
smoothly at room temperature, and gave high
diastereoselectivities and yields. Efforts to develop an
asymmetric catalyst for this reaction in ionic liquids are
currently in progress.
The recycle process was investigated (Table 4) starting
with fresh [hmim]BF4− and 4-chlorobenzaldehyde. After
the reaction was complete (monitored by TLC), the
ionic liquid and In(OTf)3 were recycled and reused in
the second cycle with the same aldehyde. The yield and
−
Table 3. In(OTf)3-catalyzed asymmetric Mannich-type reaction with various aldehydes using [hmim][BF4
]
Table 4. Recycling investigation on the asymmetric Mannich-type reaction in [hmim][BF4−] using In(OTf)3

2408
S.-L. Chen et al. / Tetrahedron Letters 44 (2003) 2405–2408
Kobayashi, S.; Iwamoto, S.; Nagayama, S. Synlett 1997,
Acknowledgements
1099–1101; (d) Manabe, K.; Mori, Y.; Wakabayashi, T.;
Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 7202–7207; (e) Manabe, K.; Mori, Y.; Kobayashi, S.
Tetrahedron 2001, 57, 2537–2544; (f) Kobayashi, S.; Busu-
jima, T.; Nagayama, S. Synlett 1999, 545–546. Selected
examples on chiral Mannich reactions: (g) Cozzi, P. G.; Di
Simone, B.; Umani-Ronchi, A. Tetrahedron Lett. 1996, 37,
1691–1694; (h) Katritzky, A. R.; Qiu, G.; He, H.-Y.; Yang
B. J. Org. Chem. 2000, 65, 3683–3689; (i) Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964–
12965. For Mannich reactions using silyl enol ethers/
ketene silyl acetals in water: (j) Loh, T. P.; Wei, L. L.
Tetrahedron Lett. 1998, 39, 323–326; (k) Loh, T. P.; Liung,
S. B. K. W.; Tan, K. L.; Wei, L. L. Tetrahedron 2000, 37,
3227–3237.
e thank the National University of Singapore for
providing the research funding, the Singapore Millen-
nium Fund for providing the research scholarship and
the National Natural Science Foundation of China
(No. 20172039).
References
1. Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH,
2000.
2. Recent review articles: (a) Sheldon, R. A. Chem. Commun.
2001, 2399; (b) Gordon, C. M. Appl. Catal. A: General
2001, 222; (c) Wasserschied, P.; Keim, W. Angew. Chem.,
Int. Ed. 2000, 39, 3772; (d) Holbrey, J. D.; Seddon, K.R.
Clean Prod. Processes 1999, 1, 223; (d) Welton, T. Chem.
Rev. 1999, 99, 2071.
3. Some selected publications on Mannich reactions in
aqueous media: (a) Akiyama, T.; Takaya, J.; Kagoshima,
H. Synlett 1999, 1426–1428; (b) Kobayashi, S.; Araki, M.;
Yasuda, M. Tetrahedron Lett. 1995, 36, 5773–5776; (c)
4. Loh, T. P.; Ho, D. S. C.; Xu, K. C.; Sim, K. Y. Tetra-
hedron Lett. 1997, 38, 865.
5. The same reaction carried out using indium trichloride in
MeOH has been shown to give comparative yields and
selectivities: Loh, T. P.; Chen, S. L. Org. Lett. 2002, 4,
3647–3650.