Silicon as a directing group in the phosphine-catalyzed [2 + 3]-cycloaddition of aryl allenones with electron-deficient olefins

Article abstract of DOI:10.1039/b819959k

This Communication describes a highly efficient phosphine-catalyzed [2 + 3]-cycloaddition reaction using α-trimethylsilyl-substituted aryl allenones and electron deficient olefins; both good yields and good asymmetric induction were obtained.

Full text of DOI:10.1039/b819959k

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Silicon as a directing group in the phosphine-catalyzed
[2 + 3]-cycloaddition of aryl allenones with electron-deficient olefinsw
Magesh Sampath and Teck-Peng Loh*
Received (in Cambridge, UK) 10th November 2008, Accepted 6th January 2009
First published as an Advance Article on the web 30th January 2009
DOI: 10.1039/b819959k
This Communication describes a highly efficient phosphine-catalyzed
[2 + 3]-cycloaddition reaction using a-trimethylsilyl-substituted aryl
allenones and electron deficient olefins; both good yields and good
asymmetric induction were obtained.
room temperature to afford the desired [2 + 3]-cyclized
product (2a) in 84% yield (Table 1, entry 1). Only a trace
amount (5% yield) of the [4 + 2] Diels–Alder product was
isolated. The reaction also worked with a wide variety of other
electron deficient olefins (Table 1, entries 2–8). Investigating
this reaction with DABCO (1,4-diazabicyclo[2.2.2]octane) or
triethylamine instead of triphenylphosphine led to no reaction.
To further explore the synthetic value of this method, we
extended it to furan-2-yl allenones 3. These are more versatile
compounds as the furan ring can be easily manipulated,11 and
results are summarized in Table 2. In all cases (Table 2,
entries 1–8), the results were similar to the reactions involving
allenone 1. This method works well with a range of electron
deficient olefins, including ethyl-4,4,4-trifluorocrotonoate
(Table 1 and Table 2, entries 7), which provided easy access
to biologically important trifluoromethyl-substituted cyclo-
pentenoids. It is important to note that the silicon group
was not retained in the final product. The stereochemistry of
the diethylmaleate (Z) (Table 1 and Table 2, entries 4) was
retained in the product, implying that the mechanism of this
cycloaddition reaction could be concerted.
Functionalized five-membered rings are featured widely in many
drugs and natural products.1 Accordingly, much effort has been
directed towards the development of new synthetic methods for
their construction.2,3 Among the methods available, the syn-
thesis of functionalized cyclopentenes via [2 + 3]-cycloaddition
reactions using allenoates, electron deficient olefins and catalytic
amounts of phosphine, first reported by Lu and Zhang in 1995,
has been shown to be one of the most powerful methods,4 and
the products can be easily derivatized into highly functionalized
cyclopentanes. In recent years, highly asymmetric versions of
this reaction have also emerged.5 Furthermore, this method
has also been applied to the total synthesis of several
natural products.6 A variation of this method via a [4 + 2]
process to construct six-membered rings has also been elegantly
demonstrated by Kwon7a,b and Fu.7c
While allenoates have been widely used,8 the corresponding
allenones have only just recently been revealed by Wallace and
Sidda.9 Although it has been shown to work with many different
aliphatic allenones, one of the major limitations of this method
is that higher Michael acceptors, such as aromatic allenones,
afford self-dimerized [4 + 2] Diels–Alder products (e.g. A)
instead of the desired [2 + 3]-cycloaddition adducts (e.g. B)
(Scheme 1).9 We envisaged that the use of a-trimethylsilyl
substituted allenones10 may solve this problem by suppressing
formation of the self-[4 + 2] adduct due to the steric bulk of the
silicon, thus affording the desired cross-[2 + 3]-cycloaddition
adduct. For a similar reason, substitution at the a-position
will lead to preferential attack at the g-position, leading to the
g-adduct. Herein, we report a highly regioselective synthesis of
functionalized cyclopentenes via [2 + 3]-cycloaddition reac-
tions using a-silyl-substituted aromatic allenones and electron
deficient olefins.
Next, we focused on a catalytic asymmetric version of this
method by screening a number of commercially available
chiral phosphines such as (+)-BINAP (0% yield, 0% ee),
(2S,3R)-CHIRAPHOS (82% yield, 22% ee), (S,S)-Et-
DUPHOS (30% yield, 60% ee), (R,R)-Et-DUPHOS (40%
yield, ꢀ70% ee), (+)-DIOP (62% yield, 10% ee) and
(S)-(ꢀ)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline
(75% yield, 37% ee). Although (S,S)-Et-DUPHOS showed
moderate enantioselectivity, the yield was low. In order to
increase the yield with (S,S)-Et-DUPHOS, different solvents
were screened. Among them, CH2Cl2 was the best, providing
the desired product in 52% yield with an improved ee of 71%
(Table 3, entry 1). Increasing the catalyst loading and adding it
slowly did not make any difference to the yield or ee of the
product. Upon cooling the reaction to ꢀ10 1C in CH2Cl2,
a
decline in rate and yield were observed with
(S,S)-Et-DUPHOS. With these optimized conditions (20 mol%
(S,S)-Et-DUPHOS, rt, in CH2Cl2), asymmetric cycloaddition
reactions using phenyl allenone 1 and furan allenone 3 with
electron deficient olefins were carried out, and the results are
Initial studies were carried out with trans-chalcones using
a-trimethylsilyl-substituted aromatic allenone 1, in the pre-
sence of a catalytic amount of triphenylphosphine (20 mol%)
in toluene. To our delight, the reaction proceeded smoothly at
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637616. E-mail: teckpeng@ntu.edu.sg;
Fax: +65 6791 1961; Tel: +65 6316 8899
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 708751. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b819959k
Scheme 1 The phosphine-catalyzed [4 + 2]-cyclization of aryl
allenones.z
ꢁc
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Table 1 Trimethylsilyl-directed [2 + 3]-cycloaddition using a phenyl allenonea
Entry
R1
R2
R3
Product (2c)b
Yield (%)c
1
2
COC6H5
4-MeCOC6H4
4-MeCOC6H4
H
COOEt
COOMe
CF3
H
H
H
COOEt
H
C6H5
2a
2b
2c
2d
2e
2f
84
75
78
72
82
80
63
52
4-EtOC6H4
4-MeC6H4
COOEt
COOEt
H
3
4d
5
6e,f
7
H
H
COOMe
COOEt
H
2g
2h
8f
CH3
a
See the ESI for the detailed experimental procedure. The relative stereochemistry of the product (2a) was identified by X-ray analysis
b
(Scheme 2). 499% of a single isomer (g) was observed by 1H NMR analysis. Isolated yield. About 5% of the self-dimerized products were
c
d
e
obtained. Diethyl maleate (Z) was used as the enone. Two regioisomeric products (2c and 2a) were observed in the ratio 5 : 1, respectively, by
1H NMR analysis. 10 mol% of enone was used.
f
yields. Interestingly, the reaction of furan allenone 3 with
trans-chalcone (Table 3, entry 2) afforded the product in a
high enantioselectivity (92% ee), which further increases the
synthetic utility of this method. Although CH2Cl2 showed
good results, isomerization12 of maleate to fumarate occurred
under these reaction conditions. In these cases, toluene was the
solvent of choice. (Table 3, entries 4 and 5)
In conclusion, we have demonstrated that the introduction
of a silicon group at the a-position of allenones is the key to
obtaining cross-cyclized [2 + 3] products. This is probably due
to steric effects that suppress the [4 + 2] self-condensation
reaction. In contrast to normal allenones, a-silyl substituted
allenones lead to the preferential formation of g adducts with
b-unsubstituted olefins such as methyl acrylate and methyl
Scheme 2 X-Ray crystal structure of 2a; 50% probability was chosen
methacrylate. In addition, entirely g adduct product was
observed with b-substituted olefins. Preliminary studies on the
asymmetric version of the reaction using (S,S)-Et-DUPHOS,
for the ellipsoids.w
shown in Table 3. In all cases, this asymmetric cycloaddition
reaction delivered high enantioselectivities and moderate
a commercially available chiral phosphine, lead to [2 + 3]
Table 2 Trimethylsilyl-directed [2 + 3]-cycloaddition using a furan-2-yl allenonea
Entry
R1
R2
R3
Product (4c)b
Yield (%)c
1
2
COC6H5
4-MeCOC6H4
4-MeCOC6H4
H
COOEt
COOMe
CF3
H
H
H
COOEt
H
C6H5
4a
4b
4c
4d
4e
4f
75
80
78
83
80
83
72
55
4-EtOC6H4
4-MeC6H4
COOEt
COOEt
H
3
4d
5
6e,f
7
H
H
COOMe
COOEt
H
4g
4h
8f
CH3
a
b
c
See the ESI for the detailed experimental procedure. 499% of a single isomer (g) was observed by 1H NMR analysis. Isolated
d
e
yield. Diethyl maleate (Z) was used as the enone. Two regioisomeric products (2c and 2a) were observed in the ratio 5 : 1, respectively, by
1H NMR analysis. 10 mol% of enone was used.
f
ꢁc
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Table 3 Asymmetric [2 + 3]-cycloaddition reactionsa,b
Entry
Allene
R1
R2
Yield (%)c
ee (%)d
1
2
3
1
3
3
3
1
COC6H5
COC6H5
4-MeCOC6H4
COOC2H5
COOC2H5
C6H5
C6H5
4-EtOC6H4
COOC2H5
COOC2H5
52
54
56
62
48
71
92
70
74
80
4e,f
5e,f
a
b
c
See the ESI for the detailed experimental procedure. The absolute stereochemistry was not determined. 499% of a single isomer (g) was
observed. Isolated yield. The ee was determined using chiral HPLC. Diethyl maleate (Z) was used as the enone. Toluene was used as solvent,
when the reaction using CH2Cl2 two regio isomeric products were observed.
d
e
f
products in moderate-to-high enantioselectivities. Further
investigations on the scope, mechanism and synthetic applica-
tions of this new approach to complex molecule synthesis are
now in progress.
5 (a) X. Zhang, G. Zhu, Z. Chen, Q. Jiang, D. Xiao and P. Cao,
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We thank Dr Yong-Xin Li for the X-ray analyses.
We gratefully acknowledge the Nanyang Technological
University and Biomedical Research Council (A*STAR Grant
no 05/1/22/19/408) for funding support this research.
Notes and references
z General procedure for the phosphine-catalyzed [2 + 3]-cycloaddition
of a-trimethylsilyl-substituted aryl allenones with electron deficient
olefins: To a stirred solution of the aryl allenone (50 mg, 0.23 mmol)
and the enone or enolate (0.25 mmol) in toluene (1.5 mL) was added,
drop-wise, the phosphine (5.3 mg, 20 mol%) (pre-dissolved in toluene)
at 0 1C under N2. After 20 h of stirring at room temperature under an
N2 atmosphere, the reaction mixture was concentrated and purified
using flash column chromatography (15–20% ethyl acetate in hexane).
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12 When CH2Cl2 or CHCl3 were used as the solvent, 30% of the other
diastereomer was observed.
A control experiment showed
that 50% of the diethyl maleate isomerized when stirred with
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ꢁc
This journal is The Royal Society of Chemistry 2009
1570 | Chem. Commun., 2009, 1568–1570