Catalytic asymmetric allylation of aldehydes via a chiral indium(III) complex

Article abstract of DOI:10.1039/b412736f

A chiral indium complex has been discovered to effect high enantioselectivities in the addition of allyltributyl stannanes to aldehydes. The allylation of a variety of aromatic, α,β-unsaturated and aliphatic aldehydes resulted in good yields and high enantioselectivities (90-96% ee). The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b412736f

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Catalytic asymmetric allylation of aldehydes via a chiral indium(III)
complex{
Yong-Chua Teo, Kui-Thong Tan and Teck-Peng Loh*
Received (in Cambridge, UK) 18th August 2004, Accepted 2nd December 2004
First published as an Advance Article on the web 21st January 2005
DOI: 10.1039/b412736f
Table 1 Evaluation of various indium reagents for the asymmetric
allylation reactiona
A chiral indium complex has been discovered to effect high
enantioselectivities in the addition of allyltributyl stannanes
to aldehydes. The allylation of
a variety of aromatic,
a,b-unsaturated and aliphatic aldehydes resulted in good yields
and high enantioselectivities (90–96% ee).
Indium
reagent
Yield
(%)b
ee
In recent years, indium(III) complexes have gained widespread
application as efficient Lewis acid catalysts for various important
organic synthetic transformations.1 The ability of some of these
complexes to catalyze organic transformations in aqueous media is
especially noteworthy.2 Accordingly, much effort has been directed
towards the development of an efficient chiral indium complex for
asymmetric transformations3 which continues to pose a challenge
to synthetic chemists.
Entry
Solvent
(%)c
1
2
3
4
5
6
7
8
a
InF3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
0
36
38
52
76
36
12
52
—
0
d
In(OiPr)3
InBr3
InCl3
73
78
92
83
73
90
InCl3
InCl3
InCl3
InCl3
e
f
The asymmetric allylation of carbonyl functionality to furnish
homoallylic alcohols has acquired a major role due to the
versatility of the products, which are important building blocks
for the synthesis of many natural products and pharmaceuticals.4
In this paper, we report our work towards the development of a
chiral indium complex for catalytic asymmetric allylation.5 To the
best of our knowledge, catalytic asymmetric allylation of carbonyl
functionality using a chiral indium(III) catalyst has never been
reported. Herein, we report the first asymmetric addition of
allyltributyl stannane to aldehydes and ketones based on the use of
a catalytic amount of chiral (S)-BINOL-In(III) complex (eqn. (1)).
Unless otherwise specified, the reaction was carried out with
allyltributyl stannane (0.5 mmol) and aldehyde (0.5 mmol) in the
presence of chiral indium(III) catalyst prepared from (S)-BINOL
(22 mol%) and InCl3 (20 mol%) in the presence of 15 mg powdered
˚
activated 4A molecular sieves in 2.5 mL of CH2Cl2. The reaction
b
mixture was kept for 4 h at 278 uC and then 16 h at r.t. Isolated
yield. Please refer to supporting information for enantiomeric
c
d
excess determination. The catalyst preparation involved refluxing
for 1 h prior to the addition of allyltributyl stannane and aldehyde.
e
˚
The reaction was carried out using 50 mg of 4A molecular sieves.
The reaction was carried out with 10 mol% catalyst loading.
f
(entry 5). The reaction carried out using 2 equivalents of
allyltributyl stannane afforded the homoallylic alcohol in 76%
isolated yield with 92% ee. It is important to note that the reaction
˚
carried out with more 4A MS resulted in the formation of the
ð1Þ
product in lower yield and enantiomeric excess (entry 6).
Moreover, the reaction carried out in chloroform was found to
afford the product in good yield with similar enantioselectivities
(entry 8). It is noteworthy that the chiral ligand, (S)-BINOL can be
easily recovered by silica gel chromatography in almost quantita-
tive yield (98%), making the amount of the chiral (S)-BINOL used
in this reaction irrelevant and the allylation process cost effective.
After determination of the optimized reaction parameters, we
extended the catalytic enantioselective addition of allyltributyl
stannane to a wide variety of aldehydes (eqn. (3)). The results
obtained are shown in Table 2.
In our initial study, we subjected benzaldehyde to a series of
experiments to evaluate the merits of various indium reagents
(eqn. (2)). The various (S)-BINOL-indium complexes were
prepared by reacting the indium salts and (S)-BINOL at room
˚
temperature in the presence of activated 4A MS. After stirring
for 2 h, allyltributyl stannane (1 equiv.) was added followed by
benzaldehyde (1 equiv.). The results obtained are shown in Table 1.
Among them, the reaction catalyzed by the (S)-BINOL-InCl3
complex exhibited the best conversion and enantiomeric excess
In all cases, the homoallylic alcohols were obtained in good
yields and high enantioselectivities (up to 96% ee) not only with
aromatic aldehydes but also with a,b-unsaturated and aliphatic
aldehydes. In the reaction with a,b-unsaturated aldehydes, the 1,2-
addition reaction proceeded exclusively. The absolute configura-
tion of the homoallylic alcohols was determined by comparison of
the sign of the optical rotation and HPLC results with the
{ Electronic supplementary information (ESI) available: spectroscopic and
analytical data for all compounds and the representative procedure. See
http://www.rsc.org/suppdata/cc/b4/b412736f/
*chmlohtp@nus.edu.sg
1318 | Chem. Commun., 2005, 1318–1320
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Table 2 Enantioselective allylations of various aldehydes catalyzed by chiral (S)-BINOL–In(III) complexa
Entry
RCHO
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
a
(E)-PhCHCH
Ph
PhCH2CH2
2-naphthyl
n-C8H17
72
76
64
55
72
53
70
96
92
90
90
94
94
94
c-C6H11
BnO(CH2)3
Unless otherwise specified, the reaction was carried out with allyltributyl stannane(1.0 mmol) and aldehyde (0.5 mmol) in the presence of
˚
chiral indium(III) catalyst prepared from (S)-BINOL (22 mol%) and InCl3 (20 mol%) in the presence of 15 mg powdered activated 4A
b
c
molecular sieves in 1.5 mL of CH2Cl2. The reaction mixture was kept for 4 h at 278 uC and then 16 h at r.t. Isolated yield. Please refer to
supporting information for enantiomeric excess determination.
literature value.6 The si face of the aldehyde is attacked when the
(S)-catalyst is used, in agreement with the constant preference
shown by BINOL-based catalysts.5
It is of mechanistic interest to note that the chiral indium
complex can function as a catalyst even though indium trichloride
has been known to undergo transmetallation reaction with allylic
1
stannanes. As such, we decided to conduct H NMR studies to
gain insight to the active species of the catalyst and understand
the origin of the high enantioselectivities. (1) The addition of
equimolar of allyltributyl stannane to the mixture of (S)-BINOL–
InCl3 indicates the formation of a quantitative set of new allylic
signal on the NMR spectrum together with tributyl stannane
chloride; nevertheless, the allylindium derivative thus formed did
not afford any detectable amounts of products upon addition of
an equimolar amount of benzaldehyde after 24 h. This study
shows that an allyl transfer from indium to aldehyde can be
excluded as the actual reaction pathway. (2) The addition of
1.0 mmol of allyltributyl stannanes to a 0.1 mmol mixture of of
(S)-BINOL–InCl3 indicates the formation of the new allylic signal
with excess allyltributyl stannanes. The intensity ratio of this new
allylic signal relative to the allyltributyl stannanes was 10:90.
Subsequent addition of 0.5 mmol benzaldehyde afforded the
product in 52% yield with 90% ee after 12 h. This study shows that
10% of allyltributyl stannanes underwent transmetallation reaction
with InCl3 and the excess allyltributyl stannane act as the allylating
reagent for the subsequent reaction. On the basis of the above
observations, we postulated that InCl3 underwent transmetallation
with allyltributyl stannane to form a new allylic species which
forms a chiral indium complex with BINOL. A (S)-BINOL–In–
allyl complex probably acts as the chiral Lewis acid for the
asymmetric allylation reaction but further mechanistic investiga-
tions are in course.
Chart 1 Non-linear effect in asymmetric allylation catalyzed by non
racemic (S)-BINOL.
either before or after the formation of the chiral active indium
complex prior to the addition of aldehydes. The reaction carried
out with the addition of water after the formation of the
active catalytic indium species resulted in the formation of the
homoallylic alcohols in 42% yield with 80% ee. On the contrary,
a racemic product was obtained in ,10% yield when water was
added prior to the formation of the active catalytic indium
˚
species. These results suggested that the addition of 4A MS is
important for high asymmetric induction and provide insights to
designing better chiral ligand for stronger complexation with the
indium salts.
In conclusion, we have demonstrated the first highly enantio-
selective addition of allylic moiety to aldehydes using a catalytic
amount of the (S)-BINOL–In(III) complex. The main features of
this reaction are as follows: (1) the procedure is operationally
simple and can furnish a wide variety of homoallylic alcohols in
good yields with high levels of enantioselectivities; (2) the allylation
can be performed exclusively by using commercially available
chemicals; (3) the chiral ligand can be recovered in high yield thus,
making this method attractive for scale-up preparation of
homoallylic alcohols with high enantioselectivities. Continuing
investigations in this laboratory will attempt to elucidate the
identity of the BINOL–In(III) species and further expand the scope
of the process.
A study with the BINOL ligand of different optical purity
exhibited no non-linear in correlating the enantiopurity of allyla-
tion product 2 (R 5 Ph) with the ee of (S)-BINOL. The results
obtained are shown in Chart 1. This study also suggested that the
BINOL–In(III) complex most probably exists as a monomeric
species in solution and even if aggregates are present, they have no
catalytic effect.
We wish to thank the National University of Singapore for their
generous financial support. Yong-Chua Teo is grateful to the
Institute of Chemical and Engineering Sciences Ltd. (ICES) for a
doctorate scholarship.
Next, we proceeded to extend the catalytic protocol to
aqueous media. The reaction was carried out by adding water
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Yong-Chua Teo, Kui-Thong Tan and Teck-Peng Loh*
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, 117543, Singapore. E-mail: chmlohtp@nus.edu.sg;
Fax: (+65) 6779 1691; Tel: (+65) 6874 7851
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1320 | Chem. Commun., 2005, 1318–1320
This journal is ß The Royal Society of Chemistry 2005