Enantioselective allylation of ketones catalyzed by chiral In(III)-PYBOX complexes

Article abstract of DOI:10.1039/b507768k

In the presence of 20 mol% of chiral catalytic complex prepared from In(OTf)₃ and chiral PYBOX, allyltributylstannane reacted with achiral ketones to afford the corresponding homoallylic alcohols in moderate to high enantioselectivities (54-95%

Full text of DOI:10.1039/b507768k

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Enantioselective allylation of ketones catalyzed by chiral
In(III)-PYBOX complexes{
Jun Lu,ac Mei-Ling Hong,c Shun-Jun Ji,*a Yong-Chua Teoc and Teck-Peng Loh*ab
Received (in Cambridge, UK) 2nd June 2005, Accepted 29th June 2005
First published as an Advance Article on the web 25th July 2005
DOI: 10.1039/b507768k
In the development of this methodology, we had screened
In the presence of 20 mol% of chiral catalytic complex prepared
from In(OTf)3 and chiral PYBOX, allyltributylstannane reacted
with achiral ketones to afford the corresponding homoallylic
alcohols in moderate to high enantioselectivities (54–95% ee),
which constitutes the first example of enantioselective allylation
of ketones catalyzed by the chiral In(III)-PYBOX complex.
several variants of the PYBOX ligand using the following standard
protocol. To an oven dried 5 mL round-bottom flask equipped
with a magnetic stirring bar was added In(OTf)3 (0.2 equiv.) and
˚
4 A molecular sieve (120 mg). The solids were azeotropically dried
with anhydrous tetrahydrofuran twice (2 mL 6 2) prior to the
addition of 1 mL of dichloromethane. Chiral PYBOX (0.22 equiv.)
was added and the mixture was stirred under nitrogen at room
temperature for 2 h to afford a white suspension. A mixture of
ketone 6 (0.15 mmol, 1 equiv.) and TMSCl (1.2 equiv.) in
dichloromethane (0.2 mL) was added to the resulting suspension
and stirred for 10 min. The mixture was then cooled to 0 uC for
15 min followed by the addition of allyltributylstannane
(1.2 equiv.). The reaction mixture was stirred at 0 uC for 70 h,
and was subsequently treated with 2 mL saturated sodium
bicarbonate solution at room temperature for 30 min. The product
was extracted with dichloromethane, washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The residual crude
product was purified via silica gel chromatography to afford the
homoallylic alcohol 7. The results for chiral PYBOX 1–5 are
summarized in Table 1.
Enantioselective allylation of carbonyl compounds is one of the
most useful tools in synthetic organic chemistry, due in part to the
fact that chiral homoallylic alcohols are very useful intermediates
for the enantioselective synthesis of complex chiral substances.1
The potential of this synthetic tool has been enhanced by newly
developed enantioselective versions, especially chiral Lewis acid-
catalyzed addition of the allyl transfer reagent to the carbonyl
functionality. It has been demonstrated that many catalysts
promote the enantioselective allylation of aldehydes to give
secondary homoallylic alcohols with excellent enantioselectivities.2
However, very few enantioselective allylation of ketones have been
successful3 owing to the significant differences in reactivity between
aldehydes and ketones. To compensate for the reduced reactivity
of ketones, a more reactive allylating agent is needed.
In recent years, indium(III) complexes have gained widespread
applications as efficient Lewis acids for various carbon–carbon
bond forming reactions and other synthetic transformations.4
Based on our previous work on the asymmetric allylation of
aldehydes,5 we have developed the first catalytic asymmetric
allylation of ketones using allyltributylstannane as an allylating
reactant based on catalytic amounts of chiral In(III)-PYBOX
complex (eqn. (1)).
ð1Þ
The best result was obtained from the use of the chiral
tetraphenyl substituted (S)-i-PrPYBOX 5 with 80% yield and
62% ee (Table 1, entry 5).
aKey Lab. of Organic Synthesis of Jiangsu Province, College of
Chemistry and Chemical Engineering of Suzhou University, Suzhou,
215006, China. E-mail: shunjun@suda.edu.cn; Fax: 86-512-65112853;
Tel: 86-512-65112371
Under the optimal conditions described above, other ketones
were examined, and the results are collected in Table 2. The
reactions of ketones with allyltributylstannane gave the corres-
ponding chiral homoallylic alcohols with moderate to good yields
(40–90%) and moderate to high enantioselectivities (up to 95% ee,
Table 2, entry 6). Attention is drawn to entries 1 and 2 in which
practically no attenuation of catalytic efficiency and enantio-
selectivity was observed by reusing the recovered chiral ligand.
bDivision of Chemistry and Biological Chemistry, Nanyang
Technological University, Singapore 637616.
E-mail: teckpeng@ntu.edu.sg; Fax: 65-6316 6984; Tel: 65- 6790 3733
cDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore 117543
{ Electronic supplementary information (ESI) available: Spectroscopic
and analytical data for all compounds and the representative procedure.
See http://dx.doi.org/10.1039/b507768k
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4217–4218 | 4217

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product. It is worthy to note that the catalytic allylation of ketones
for our chiral indium complex can be accomplished simply by
using allyltributyl stannane unlike other catalytic systems that
require stronger allylating reagents such as tetraallylstannanes.
In summary, we have developed a novel and practical
enantioselective catalytic system for the allylation of ketones that
provides tertiary homoallylic alcohols with moderate to high
Table 1 Evaluation of various chiral indium(III) complexes for the
asymmetric allylation reaction
Entry
PYBOX
Ketone
Yield (%)a
ee (%)b
enantiomeric excess using
a catalytic amount of chiral
In(III)-PYBOX complex. In some cases, the corresponding
allylation products could be obtained in ¢90% ee. Further efforts
are being directed toward exploring the utility of this novel
approach and the mechanism of the chiral indium–PYBOX
complex catalysed allylation reaction.{
We thank the Nanyang Technological University and the
National Natural Science Foundation of China (No. 20472062)
for providing the research funding.
1
2
3
4
5
a
1
2
3
4
5
b
PhCOCH3
PhCOCH3
PhCOCH3
PhCOCH3
PhCOCH3
20
10
30
34
80
20
26
27
31
62
Isolated yield. ee determined by HPLC.
The conjugated enone undergoes exclusively 1,2-addition in
good yield and with fair enantiomeric excess (Table 2, entry 5), the
saturated derivative reacted to give the homoallylic alcohol with
nearly the same enantiomeric excess (Table 2, entry 4). Excellent
results were obtained when cyclic ketones were used as starting
materials (Table 2, entries 6, 7, 8). During the study, we found the
role of TMSCl was crucial for the reaction, the absence of which
will result in a dramatic decrease in enantioselectivity and yield of
Notes and references
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Table 2 Enantioselective allylation of ketones catalyzed by In(OTf)3-
PYBOX 5 complexa
Entry
1
Ketone
Yield (%)b
80d
ee (%)c
62 R
2
3
4
5
79
85
80
71
63e R
67 R
55 S
54 R
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6
7
8
90
40
68
95 R
90 R
84 R
a
All the reactions were carried out with ketone (1 equiv.), TMSCl
(1.2 equiv.) and allyltributylstannane (1.2 equiv.) using In(OTf)3
(0.2 equiv.) and (S)-i-PrPYBOX 5 (0.22 equiv.) in the presence of
˚
activated MS 4 A in anhydrous CH2Cl2. The reaction mixture was
b
c
kept for 70 h at 0 uC. Isolated yield. ee determined by HPLC, the
absolute configuration of products was assigned by comparison with
optical rotation and/or retention time on chiral HPLC in ref. 6. For
d
further details see supporting information. 85% of chiral ligand
was recovered. Recovered (S)-i-PrPYBOX 5 was used for the
reaction.
e
6 Y.-C. Teo, J.-D. Goh and T.-P. Loh, Org. Lett., 2005, 13, 2743.
4218 | Chem. Commun., 2005, 4217–4218
This journal is ß The Royal Society of Chemistry 2005