Phosphine oxides as efficient neutral coordinate-organocatalysts for stereoselective allylation of N-acylhydrazones

Article abstract of DOI:10.1039/b315037b

Phosphine oxides were found to be efficient neutral coordinate-organocatalysts (NCOs) for the allylation of N-acylhydrazones. Among the phosphine oxides tested, a three carbon-tethered bisphosphine oxide (dppp dioxide) was found to be the most effective,

Full text of DOI:10.1039/b315037b

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Phosphine oxides as efficient neutral coordinate-organocatalysts
for stereoselective allylation of N-acylhydrazones
Chikako Ogawa, Hideyuki Konishi, Masaharu Sugiura and Sh u¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan. E-mail: skobayas@mol.f.u-tokyo.ac.jp; Fax: ϩ81-3-5684-0634;
Tel: ϩ81-3-5841-4790
Received 21st November 2003, Accepted 5th January 2004
First published as an Advance Article on the web 16th January 2004
Phosphine oxides were found to be efficient neutral
coordinate-organocatalysts (NCOs) for the allylation of
N-acylhydrazones. Among the phosphine oxides tested,
a three carbon-tethered bisphosphine oxide (dppp dioxide)
was found to be the most effective, and in the presence of
dppp dioxide, less reactive aromatic and ꢀ,ꢁ-unsaturated
N-acylhydrazones underwent allylation as well as diastereo-
selective crotylation. Furthermore, a polymer-supported
phosphine oxide was also developed as an effective
immobilized NCO.
Table 1 Effect of the structure of phosphine oxide
Metal-free organic molecule-catalyzed reactions have been
widely focused on because of their stability and environ-1
mentally benign nature compared to metal complex-catalysts.
In the allylation of aldehydes using allyltrichlorosilanes, Lewis
1
2
Entry
R
R
Phosphine oxide
Ph P᎐O
Yield/%
1
2
3
4
5
6
PhCH
CH
H
H
H
H
Cl
CF3
72
57
4
5
79
67
2
2
3
n
2
3
Bu P᎐O
bases such as N,N-dimethylformamide (DMF), ureas, pyr-
3
᎐
c
4
5
6
Hex
3
P᎐O
idine N-oxides, phosphoramides, phosphine oxides, and
(o-Tol) P᎐O
7
3
sulfoxides have been reported to be effective as catalysts. In
Ph P᎐O
3
these reactions, allyltrichlorosilanes form an active hypervalent
silicon species by coordination of the Lewis base serving
Ph P᎐O
3
8
as nucleophile. We previously defined these Lewis bases as
7
8
9
Ph
Ph
Ph
OMe
Ph
Bu P᎐O
3
P᎐O
3
3
12
24
n
neutral coordinate-organocatalysts (NCOs) so that they can be
Ph P᎐O
3
distinguished from anionic Lewis bases such as alkoxide and
9
halide anions.
As for the allylation of azomethine compounds such as N-(2-
10
hydroxyphenyl)imines and N-acylhydrazones, we have found
7
several types of effective NCOs. Among them, sulfoxides were
found to be one of the most effective NCOs, and enantio-
selective allylations have been successfully achieved using chiral
sulfoxides such as (ϩ)-methyl p-tolyl sulfoxide, though three
equivalents of sulfoxides and 2-methyl-2-butene as an acid
scavenger were required in that system because of the low
stability of sulfoxides under acidic conditions. Herein, we
report phosphine oxides as further advanced NCOs in the
allylation of N-acylhydrazones. Phosphine oxides are more
11
stable under acidic or oxidative conditions than sulfoxides.
At the outset, the reactions of typical aromatic and aliphatic
N-benzoylhydrazones with allyltrichlorosilane (1.5 equiv.) were
performed in the presence of one equivalent of a phosphine
oxide (Table 1). It was found that triphenylphosphine oxide was
the most effective among the NCOs tested in the reaction with
3
-phenylpropanal-derived N-benzoylhydrazone as a substrate
(
Table 1, entry 1), while benzaldehyde-derived N-benzoyl-
hydrazones gave lower yields (entries 7–9).
We then conducted a kinetic study at the initial stage of allyl-
ation of an aliphatic N-benzoylhydrazone using different
equivalents of triphenylphosphine oxide ranging from 50 mol%
to 300 mol%, and the results are shown in Fig. 1. With
increasing equivalents of NCO up to 200 mol%, the yield got
significantly better. However, the use of 300 mol% phosphine
oxide did not improve the yield. It was suggested that two NCO
molecules coordinated to allyltrichlorosilane to facilitate the
Fig. 1 Effect of the amount of Ph P᎐O.
᎐
3
4
46
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 4 6 – 4 4 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Effect of methylene-tethered bisphosphine oxides
Scheme 1 Polymer-supported NCOs.
(
entries 6, 7, 10, and 13), it should be noted that yields were
rather improved by using dppp dioxide instead of dimethyl
sulfoxide which we previously utilized as an NCO.
a
7,13
n
1
6
2
3
4
3
5
6
3
Finally, we investigated immobilization of a phosphine oxide
on a polymer-support. We have already reported polymer-
supported (PS)-formamide 1 (Scheme 1) as a recoverable and
reusable NCO, which worked well in the allylation of aldehydes
Yield/%
a
15
71
23
24
45
5
0 mol% of phosphine oxide was used.
14
with allyltrichlorosilane. Although PS-formamide was the
first example of an immobilized NCO, it showed lower activity
in the allylation of N-acylhydrazones. Therefore, we tried to
develop PS-phosphine oxides as more effective immobilized
NCOs. PS-phosphine oxide 2 (Scheme 1) was readily prepared
from oxidation of commercially 1 available PS-phosphine
reaction. Meanwhile, Denmark and his co-workers investigated
the mechanism of allylation of aldehydes with allyltrichloro-
silanes using phosphoramides as NCOs. They concluded that
the allylation was promoted via activation of the silane by two
phosphoramide molecules. Based on these results, we next
decided to examine the effect of methylene-tethered bis-
phosphine oxides on the selectivity and reactivity of the
reactions (Table 2). It was found that by changing the length of
the tether, the yield was dramatically changed. When one
equivalent of 1,3-bis(diphenylphosphino)propane dioxide (n =
12
5
using hydrogen peroxide in acetone. The completion of the
31
oxidation was confirmed by the P swollen resin magic angle
16
spinning NMR (SR-MAS NMR). The loading level of
17
the phosphine oxide was determined by elemental analysis.
Allylation of 3-phenylpropanal-derived benzoylhydrazone
using 2 (2.0 equiv.) afforded the desired product quantitatively
3
, dppp dioxide) was used, the best yield was obtained, while in
18
(
Scheme 2).
the case of n = 4, the reaction scarcely proceeded possibly
because of poor solubility of the NCO.
We then examined substrate generality using dppp dioxide as
an NCO (Table 3).† Aliphatic, aromatic, and α,β-unsaturated
N-acylhydrazones underwent allylation and stereospecific
crotylation in the presence of dppp dioxide. While syn-adducts
were obtained stereoselectively from (E)-crotyltrichlorosilane,
anti-adducts were found preferentially from (Z)-crotyl-
trichlorosilane. A higher concentration (0.3 M relative to a
hydrazone) improved the yield significantly (entry 1 vs. 2).
Although the yields were still unsatisfactory in some cases
Scheme 2 Allylation of a N-acylhydrazone using PS-phosphine
oxide 2.
Table 3 Allylation and crotylation of N-acylhydrazones using dppp dioxide
1
2
3
4
Entry
R
R
R
R
Conc./M
Time/h
syn/anti
Yield/%
1
2
3
4
PhCH CH
H
H
H
H
H
H
Me
H
H
H
H
Me
0.15
0.3
0.3
0.3
1
1
6
6
—
—
98/2
<1/>99
46
quant.
88
2
2
quant.
5
6
7
Ph
OMe
OMe
OMe
H
Me
H
H
H
Me
0.3
0.3
0.3
6
6
6
—
80/20
<1/>99
87
16
60
8
9
0
PhCH᎐CH
PhC᎐C
H
H
H
H
Me
H
H
H
Me
0.3
0.3
0.3
6
6
6
—
99/1
15/85
90
85
23
1
1
1
1
1
2
3
H
H
H
H
Me
H
H
H
Me
0.3
0.3
0.3
6
6
6
—
99/1
<1/>99
92
83
55
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 4 6 – 4 4 8
447

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In conclusion, we have introduced phosphine oxides as novel
NCOs in the allylation of N-acylhydrazones. Phosphine oxides
are more stable and active than sulfoxides, and several problems
observed in the allylation using sulfoxide have been overcome.
Furthermore, a polymer-supported phosphine oxide has been
developed as a more effective immobilized NCO. A mechanistic
study and asymmetric reactions using the novel NCOs are now
in progress.
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5
6
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9
H. Sakurai, Synlett, 1989, 1.
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Acknowledgements
This work was partially supported by CREST and SORT,
Japan Science Technology Agency (JST), and a Grant-in-Aid
for Scientific Research from Japan Society of the Promotion of
Science (JSPS).
1
12, 257.
1
1
1
0 M. Sugiura, F. Robvieux and S. Kobayashi, Synlett, 2003, 1749.
1 O. D. Lucci, Org. React., 1991, 40, 157.
2 S. E. Denmark and J. Fu, J. Am. Chem. Soc., 2000, 122, 12021;
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3 We also tested these reactions using three equivalents of DMSO.
In the case of the aromatic substrate, the desired products were
hardly obtained; Z-crotylation 9% (syn/anti = 3/97), E-crotylation
1
Notes and references
†
General procedure. To a mixture of N-acylhydrazone (0.3 mmol) and
3
% (syn/anti = not determined). As for the α,β-unsaturated
phosphine oxide (1.0 equiv.) in dichloromethane (0.8 mL) was added
allyltrichlorosilane (1.5 equiv.) in dichloromethane (0.2 mL) at Ϫ78 ЊC,
and the mixture was stirred for 1–6 h. Then, triethylamine (0.2 mL) in
methanol (1.0 mL) was added to quench the reaction. After addition of
water, the mixture was extracted with dichloromethane. The organic
layers were washed with brine, dried over Na SO , filtered, and concen-
trated under vacuum. The product was isolated by silica gel
chromatography.
substrate, even allylation did not proceed using DMSO.
1
1
4 C. Ogawa, M. Sugiura and S. Kobayashi, Chem. Commun., 2003,
1
92.
®
5 Triphenylphosphine polystyrene (Novabiochem , polymer matrix:
copoly(styrene–1% DVB), 100–200 mesh) was oxidized according to
the reported procedure: T. Shimada, H. Kurushima, Y.-H. Cho and
T. Hayashi, J. Org. Chem., 2001, 66, 8854.
2
4
1
1
6 S. Kobayashi and M. Moriwaki, Tetrahedron Lett., 1997, 38, 4251.
7 The elemental analysis showed that PS-phosphine oxide 2 contained
4.2% phosphorous atoms.
18 PS-phosphine oxide 2 is not soluble but swollen in dichloromethane.
After the reaction, 2 was recovered quantitatively by simple filtration
and washing (water, methanol, diethyl ether, tetrahydrofuran, and
dichloromethane). It might be possible that one or two phosphine
oxide components in 2 activate allyltrichlorosilane in the transition
state, though the latter might be less prominent in the polymer
matrix.
1
2
For a review on enantioselective organocatalysts, see: P. I. Dalko
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5
5, 997.
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0, 3633.
M. Nakajima, M. Saito and S.-I. Hashimoto, J. Am. Chem. Soc.,
3
4
4
4
48
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 4 6 – 4 4 8