Phosphazene base-catalyzed condensation of trimethylsilylacetate with carbonyl compounds

Article abstract of DOI:10.1039/b606056k

The t-Bu-P4 base was found to be an excellent catalyst for the condensation of trimethylsilylacetate or trimethylacetonitrile with carbonyl compounds to form functionalized alkenes and β-enaminoesters were also synthesized by the condensation with formanilides. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606056k

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COMMUNICATION
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Phosphazene base-catalyzed condensation of trimethylsilylacetate with
carbonyl compounds{
Koji Kobayashi, Masahiro Ueno and Yoshinori Kondo*
Received (in Cambridge, UK) 28th April 2006, Accepted 25th May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b606056k
In our initial investigation for the condensation reaction, we
chose the reaction of ethyl trimethylsilylacetate with benzophenone
(1). When the reaction of 1 and ethyl trimethylsilylacetate in THF
in the presence of 10 mol% t-Bu-P4 base was carried out at 278 uC,
the condensation reaction proceeded smoothly and the unsatu-
rated ester (2) was isolated in 94% yield (Table 1, entry 1). Other
phosphazene bases with weaker basicity such as t-Bu-P2 base and
BEMP showed no effect on the condensation under the same
reaction conditions (Table 1, entries 2 and 3). DBU also showed
no catalytic effect on the condensation (Table 1, entry 4). When
tetrabutylammonium fluoride (TBAF) was used for the reaction,
the 1,2-adduct was isolated in 38%, but no formation of alkene
was observed (Table 1, entry 5).
The t-Bu-P4 base was found to be an excellent catalyst for the
condensation of trimethylsilylacetate or trimethylacetonitrile
with carbonyl compounds to form functionalized alkenes and
b-enaminoesters were also synthesized by the condensation with
formanilides.
Condensation of a-silylalkyl compounds with carbonyl com-
pounds to form alkenes has been known as the Peterson
olefination reaction.1 Usually an a-silanyl carbanion generated
in situ using a stoichiometric metallic base such as LDA or an
alkyllithium has been utilized for the reaction. The reaction has
been widely employed as an important method for alkene
synthesis, because of simpler workup and purification procedure
than the Wittig reaction. This condensation reaction will be
more valuable if the transformation can be accomplished with a
catalytic base.
Table 1
Phosphazene bases2 developed by Schwesinger and proazapho-
sphatranes3 developed by Verkade are known as strong non-
metallic organic superbases (Fig. 1). Among them, t-Bu-P4 base
shows extremely high basicity and has been used for various
selective deprotonative transformations.4 The strong affinity of
t-Bu-P4 base to protons is regarded as synthetically useful,
however the ability of t-Bu-P4 base to activate a-silylalkyl
compounds has not been reported. In connection with our recent
interest on the catalytic activation of organosilicon compounds
using t-Bu-P4 base,5 we investigated catalytic condensation
reactions of a-silylalkyl compounds with carbonyl compounds in
the presence of the catalytic t-Bu-P4 base.
Entry
Base
Time/h
Yield (%)
1
2
3
4
5
a
t-Bu-P4 base
t-Bu-P2 base
BEMP
DBU
TBAF
6
24
24
24
6
94
0
0
0
0 (38)a
b-Trimethylsilyloxy ester was obtained in 38% yield.
As shown in Table 1, it was found that t-Bu-P4 base is an
excellent catalyst for the condensation, and in order to examine
further scope and limitations, reactions using other substrates were
investigated. As another trimethylsilylalkyl substrate, N,N-diethyl-
trimethylsilylacetamide was reacted with 1 to give the unsaturated
amide 4a in 87% yield (Table 2, entry 1) and the reaction of
trimethylsilylacetonitrile with 1 was also successful to give 4b in
78% yield (Table 2, entry 2). Benzaldehyde (3a) was then used as a
carbonyl compound and ethyl cinnamate (4c) was obtained in 89%
yield using ethyl trimethylsilylacetate (Table 2, entry 3).
Condensation of other arylaldehydes (3b,c,d) with ethyl trimethyl-
silylacetate proceeded smoothly and the corresponding arylacry-
lates (4d,e,f) were obtained in good yields (Table 2, entries 4,5,6).
The double bonds of the products from arylaldehydes were E
geometry. When acetophenone (3e) was used as a carbonyl
compound, the reaction with trimethylsilylacetonitrile proceeded
smoothly to give the alkene (4h) in 63% yield as an E,Z mixture
(E : Z = 89 : 11) (Table 2, entry 8), however the reaction with ethyl
trimethylacetate gave the b-trimethylsilyloxy ester (4g) in 29% yield
Fig. 1 Organic strong bases.
Graduate School of Pharmaceutical Sciences, Tohoku University,
Aramaki Aza Aoba 6-3, Aoba-ku, Sendai, 980-8578, Japan.
E-mail: ykondo@mail.pharm.tohoku.ac.jp; Fax: 81-22-795-6804;
Tel: 81-22-795-6804
{ Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for synthesized compounds. See DOI:
10.1039/b606056k
3128 | Chem. Commun., 2006, 3128–3130
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Table 2
Entry
Substrate
R
R9
EWGd
Time/h
4
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
Ph
Ph
Ph
Ph
Ph
H
H
H
H
Me
Me
CONEt2
CN
12
6
6
6
6
6
6
13
6
13
6
4a
4b
4c
4d
4e
4f
87a
78
89
91
3a
3b
3c
3d
3e
3e
3f
3f
3g
COOEt
COOEt
COOEt
COOEt
COOEt
CN
COOEt
CN
COOEt
4-MeC6H4
4-MeOC6H4
2-furyl
Ph
Ph
Ph
69
85
4gb
4h
4i
(29)b
63c
81
CHLCHPh(E)
CHLCHPh(E)
H
10
11
a
Ph
n-Pentyl
4j
4k
80c
35
b
The reaction was carried out at room temperature followed by 50 uC. The 1,2-adduct, b-trimethylsilyloxy ester (4g) was isolated in 29%
c
d
yield. The reaction was carried out at 278 uC followed by 50 uC. EWG = electron withdrawing group.
(Table 2, entry 7). The reaction of chalcone (3f) with trimethyl-
silylacetate gave the diene (4i) in 81% yield (E : Z = 100 : 0)
(Table 2, entry 9). Similarly, the condensation of 3f with trimethyl-
silylacetonitrile also gave the corresponding diene (4j) in 80% yield
(E : Z = 50 : 50) (Table 2, entry 10). As an example of aliphatic
aldehyde, n-hexanal 3g was used as a substrate and the desired
unsaturated ester 4k was obtained in 35% yield (Table 2, entry 11).
Enolizable substrates seem unfavorable for this condensation.
Our next interest was focused on the condensation of
formanilides with a-trimethylsilylalkyl compounds because the
examples of enamine synthesis using the Peterson reaction are
few.6 No precedent example for the condensation of formamides
with a-trimethylsilylalkyl compounds have appeared to the best of
our knowledge.7
trimethylsilylacetate in THF at room temperature, the condensa-
tion proceeded smoothly and the enaminoester (6a) was obtained
in 90% yield (Table 3, entry 1). The same condensation was
also carried out under solvent free conditions and 6a was obtained
in 92% yield (Table 3, entry 2). Similarly trimethylsilylacetonitrile
was condensed with 5a to give the enaminonitrile (6b) in 78%
(Table 3, entry 3). Various substituents on the aromatic ring of
the formanilides were compatible with this condensation
(Table 3, entries 4–9) and the tolerance of alkoxycarbonyl group
and cyano group during the condensation is considered to be
synthetically important. N-Allyl and N-benzyl formanilides were
also reacted with trimethylsilylalkyl compounds to give the
corresponding enamines (6i–l) (Table 3, entries 10–13).
On the mechanism of the condensation, two different types
of the initial activation of trimethylsilylalkyl compounds can
be speculated. One is the deprotonative activation of the carbon–
hydrogen bond and the other is direct carbon–silicon bond
activation. Mechanism A is based on the activation of the carbon–
silicon bond by t-Bu-P4 base and ethyl trimethylsilylacetate (a) is
reacted with t-Bu-P4 base to form the reactive anion b. 1,2-
Addition of b gives c and the oxy anion of the adduct c is
silylated to form the silyl ether d. The deprotonation of d with
t-Bu-P4 base gives the carbanion e, which eliminates trimethyl-
silyloxy anion to form the desired alkene f. Here the formation of
phosphazenium silanoxide g is important and g is considered to
catalyze the elimination reaction of d to give f as well as the P4
base. This mechanism is different from the pathway of conven-
tional Peterson olefination and from our other examples on the
activation of the carbon–silicon bond using t-Bu-P4 base,5
mechanism A seems to be acceptable as a candidate. In this
mechanism, t-Bu-P4 base catalyzes the initial 1,2-addition and in
the elimination both t-Bu-P4 base and phosphazenium silanoxide
g act as catalysts.
Table 3
Yield
Entry Substrate X
R
EWG Time/h 6 (%)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5b
5c
5d
5d
5e
5e
5f
H
H
H
Me
OMe
COOEt Me
COOEt Me
CN
CN
H
Me
Me
Me
Me
Me
COOEt 24
COOEt 24
6a 90
6a 92a
6b 78a
6c 74
6d 47
6e 85
6f 87
6g 80
6h 80
6i 83a
6j 42a
6k 99a
6l 88a
CN
24
COOEt 48
COOEt 48
COOEt 24
CN
COOEt 20
CN 48
48
Me
Me
10
11
12
13
a
CH2CHLCH2 COOEt 24
24
COOEt 24
CN 24
5f
5g
5g
H
H
H
CH2CHLCH2 CN
CH2Ph
CH2Ph
Mechanism B is based on the initial deprotonation of ethyl
trimethylsilylacetate (a) and the carbanion b9 is first formed.
The 1,2 addition of b9 gives the alkoxide c9 which TMS rearranges
to oxygen to give the carbanion e. The elimination reaction of e
gives the alkene f. The phosphazenium silanoxide g is also used
in the deprotonation of a in the following catalytic cycles. In
Solvent free reaction.
Compared to ketones or aldehydes, the reactivities of for-
mamides to nucleophiles were considered to be lower and the
investigation was started with the reaction at room tempera-
ture. When N-methylformanilide (5a) was reacted with ethyl
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Notes and references
1 (a) L. F. van Staden, D. Gravestock and D. J. Ager, Chem. Soc. Rev.,
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D. J. Peterson, J. Org. Chem., 1968, 33, 780–784.
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J. Boele, H. Fritz, D. Putzas, H. W. Rotter, F. G. Bordwell, A. V. Satish,
G.-Z. Ji, E.-M. Peters, K. Peters, H. G. von Schnering and L. Walz,
Liebigs Ann., 1996, 1055–1081.
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8479–8483; (e) H. Schlaad, H. Kukula, J. Rudloff and I. Below,
Macromolecules, 2001, 34, 4302–4304; (f) T. Imahori and Y. Kondo,
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both mechanisms, the role of the phosphazenium silanoxide g
is important and g has the highly delocalized, large cation and
the counter anion is considered to show highly ionic character
which is favorable for deprotonation. The formation of the
reactive phophazenium intermediates is considered to be the
big difference from the situation using conventional ionic bases.
At this point we do not have experimental evidence to
determine which mechanism is operating in the reaction, and
the NMR analysis of the reaction of trimethylsilylalkyl
compounds with t-Bu-P4 base has not given us any suggestive
evidence.
In summary, t-Bu-P4 base was found to be an effective
catalyst for the condensation of functionalized trimethylsilylalk-
anes with carbonyl compounds, and the selective alkene formation
was accomplished. Further investigations on the scope and
limitation of the t-Bu-P4 base promoted condensation are in
progress and the mechanistic studies on this olefination are also
underway.
5 M. Ueno, C. Hori, K. Suzawa, M. Ebisawa and Y. Kondo, Eur. J. Org.
Chem., 2005, 1965–1968.
6 (a) W. Adam and C. M. Ortega-Schulte, Synlett, 2003, 414–416; (b)
R. Dalpozzo, A. De Nino, E. Iantorno, G. Bartoli, M. Bosco and
L. Sambri, Tetrahedron, 1997, 53, 2585–2590; (c) R. Vohra and D. B.
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7 For recent novel olefination of formamides, see: G. S. Nandra, P. S. Pang,
M. J. Porter and J. M. Elliott, Org. Lett., 2005, 7, 3453–3455.
This work was partly supported by the Grant-in Aid for
Scientific Research (No. 16659002, No. 16033208, No. 16390002)
from the Ministry of Education, Science, Sports and Culture,
Japan and a grant from the Sumitomo Foundation.
3130 | Chem. Commun., 2006, 3128–3130
This journal is ß The Royal Society of Chemistry 2006