Acyl polysilanes: New acyl anion equivalents for additions to electron-deficient alkenes

Article abstract of DOI:10.1021/ol900813z

Silenes, generated through thermolysis of acylpolysilanes, add to α,β-unsaturated esters to form cyclobutanes and silylsubstituted cyclopropanes In moderate yields. Upon Si-C bond oxidation the cyclopropanes are converted directly to 1,4-dicarbonyl compou

Full text of DOI:10.1021/ol900813z

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2744-2747
Acyl Polysilanes: New Acyl Anion
Equivalents for Additions to
Electron-Deficient Alkenes
Justin Bower,‡ Matthew R. Box,‡ Michal Czyzewski,† Andres E. Goeta,† and
Patrick G. Steel*,†
Department of Chemistry, Science Laboratories, Durham UniVersity, South Road,
Durham DH1 3LE, U.K., and Astra Zeneca, Alderley Park, Macclesfield, Cheshire
SK10 4TG, U.K.
p.g.steel@durham.ac.uk
Received April 14, 2009
ABSTRACT
Silenes, generated through thermolysis of acylpolysilanes, add to r,ꢀ-unsaturated esters to form cyclobutanes and silylsubstituted cyclopropanes
in moderate yields. Upon Si-C bond oxidation the cyclopropanes are converted directly to 1,4-dicarbonyl compounds, thus demonstrating
the formal acyl anion chemistry of acyl polysilanes.
The addition of an acyl anion to an R,ꢀ-unsaturated carbonyl
compound is a classical and valuable method to generate
synthetically useful 1,4-dicarbonyl compounds.1 Its simplest
form, the Stetter reaction, involves cyanide or thiazolium
salt promoted addition of an aldehyde to the acceptor enone.2
However, the high reactivity of the aldehyde under these
conditions can result in problems owing to self-condensation,
and consequently, many alternative acyl anion equivalents
have been described. One such class of acyl anion equivalents
are the acyl silanes, which have found widespread application
in synthesis.3 While these have proven to be effective for
Stetter-type reactions,4 in many cases their application requires
the use of basic or toxic promoters such as cyanide or fluoride.
In this Letter we describe the application of acyl polysilanes as
a neutral, thermally activated acyl anion equivalent for the
addition to R,ꢀ-unsaturated carbonyl compounds.
As part of a general program exploring the use of silenes,
compounds containing a CdSi bond, in synthesis,5-8 we had
previously explored the thermal [4 + 2] cycloaddition of
Brook-type silenes [R(R′3SiO)CdSi(SiR′3)2] with various
alkyl-substituted dienes. These proceeded as predicted to
afford the corresponding silacyclohexene in good yields and
moderate diastereoselectivity (Scheme 1).7
Although initial experiments had suggested that electron-
deficient dienes behaved similarly, a more detailed analysis
(5) Ottosson, H.; Steel, P. G. Chem.-Eur. J. 2006, 12, 1576–1585
.
(6) Pullin, R. D. C.; Sellars, J. D.; Steel, P. G. Org. Biomol. Chem.
2007, 5, 3201–3206. Hughes, N. J.; Pullin, R. D. C.; Sanganee, M. J.; Sellars,
J. D.; Steel, P. G.; Turner, M. J. Org. Biomol. Chem. 2007, 5, 2841–2848.
Sellars, J. D.; Steel, P. G. Org. Biomol. Chem. 2006, 4, 3223–3224. Sellars,
J. D.; Steel, P. G.; Turner, M. J. Chem. Commun. 2006, 2385–2387. Berry,
M. B.; Griffiths, R. J.; Sanganee, M. J.; Steel, P. G.; Whelligan, D. K.
‡ Astra Zeneca.
† Durham University.
(1) Johnson, J. S. Curr. Opin. Drug DiscoVery DeV. 2007, 10, 691–
703. Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–258.
(2) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639–647.
(3) Patrocinio, A. F.; Moran, P. J. S. J. Braz. Chem. Soc 2001, 12, 7–
31. Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. ReV. 1990, 19,
147–195. Ricci, A.; Deglinnocenti, A. Synthesis 1989, 647–660.
(4) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2004, 126, 2314–2315.
Tetrahedron Lett. 2003, 44, 9135–9138
.
(7) Berry, M. B.; Griffiths, R. J.; Sanganee, M. J.; Steel, P. G.; Whelligan,
D. K. Org. Biomol. Chem. 2004, 2, 2381–2392. Batsanov, A. S.; Clarkson,
I. M.; Howard, J. A. K.; Steel, P. G. Tetrahedron Lett. 1996, 37, 2491–
2494
(8) Sanganee, M. J.; Steel, P. G.; Whelligan, D. K. Org. Biomol. Chem.
2004, 2, 2393–2402
.
.
10.1021/ol900813z CCC: $40.75
Published on Web 05/29/2009
 2009 American Chemical Society

Scheme 1
.
Reaction of Siloxysilenes with Alkyl-Substituted
Dienes
of the reaction mixture suggested that the process was more
complex, involving the formation of isomeric silacyclobu-
tanes through a [2 + 2] cycloaddition pathway. Consequently
we re-examined this process heating pivaloyl polysilane 4
with (E,E)-diethylhexa-2,4-dienoate 5 in benzene in a sealed
tube at 170 °C for 2 h (Scheme 2). Following flash
Figure 1. (a) X-ray structure for 8. (b) Selected NOESY correlations
for 6 and 7.
results. Ultimately, the optimum reaction conditions involved
heating the polysilane 4 with a 4-fold excess of the diene at
200 °C for 3 h, which afforded a 1.9:0:2.7:1 mixture of
isomers in 69% yield, (Table 1 entry 2). The minor
silacyclobutane isomer was only observed at lower temper-
atures, while prolonged heating resulted in diminished yields
probably due to product decomposition. This suggested that
silacyclobutanes are potential intermediates on the reaction
pathway. In support of this, heating a solution of silacy-
clobutane 6 in benzene at 200 °C for 1.5 h afforded the
cyclopropane 8 in 25% yield along with 46% unchanged
silacyclobutane 6 (Scheme 3). Intrigued by this unusual
cyclopropanation we then examined other electron-deficient
silenophiles (Table 1 entries 1-10). With the exception of
phenyl vinyl sulfone (entry 9), which afforded only cyclobu-
tanes, and chalcone 11 (entry 10), all of these substrates led
to the preferential if not exclusive formation of the cyclo-
propane. The reaction with chalcone 11 produced the [4 +
2] adduct 12 in which the R,ꢀ-unsaturated enone had behaved
as the 4π component (Scheme 4). While this latter outcome
is consistent with the earlier reports by Brook describing the
reaction of photochemically generated siloxysilenes with
enals and enones, the formation of cyclopropanes contrasts
with similar studies examining reactions with cinnamate
esters.9 The reasons for this difference in reaction outcome
between these two approaches to silene generation are not
obvious and remain a subject of ongoing investigation.10 In
order to avoid the need for sealed tube apparatus, we then
explored the potential to undertake the same conversion in
a microwave vessel. Whereas for the reaction of pivaloyl
polysilane and diethyl hexadienoate, it was initially found
that by running the reaction at higher temperature (220 °C)
Scheme 2
.
Initial Thermal Reaction of Pivaloylpolysilane 4 with
Diethyl Hexadienedioate 5
chromatography, two discrete fractions could be obtained,
each containing a mixture of two diastereoisomers in an
overall 32% yield. The structures of these compounds were
determined by 2D NMR spectroscopy and, ultimately, by
single crystal X-ray diffraction of compound 8 (Figure 1a).
The configuration of the silacyclobutanes 6 and 7 could be
deduced from 2D NMR correlation experiments (Figure 1b).
The regiochemistry of the “cycloaddition” was confirmed
by HMBC experiments that, for both isomers, showed a
3-bond correlation from proton 1′-H to ring carbon C-2, and
stereochemistry was elucidated through 1H NOESY experi-
ments.
(9) Brook, A. G.; Hu, S. S.; Chatterton, W. J.; Lough, A. J. Organo-
metallics 1991, 10, 2752–2757. Brook, A. G.; Hu, S. S.; Saxena, A. K.;
Lough, A. J. Organometallics 1991, 10, 2758–2767.
(10) A model study in which a mixture of acylpolysilane 10, ethyl
cinnamate and 1,3-pentadiene were heated in benzene produced a mixture
of cyclopropane 13d and the expected adduct arising from [4 + 2]
cycloaddition of a siloxysilene with pentadiene.
Attempts to enhance the reaction by varying the reaction
temperature, time, and ratio of the reagents produced variable
Org. Lett., Vol. 11, No. 13, 2009
2745

Table 1. Thermal Reactions of Acyl Polysilanes with Electron-Deficient Alkenes
yield (%)b
cyclopropanes
entry
R1
R2
CO2Me
CHdCH CO2Et
CHdCHMe
R3
methoda
cyclobutanes
23 (1.9:0)
1
2
3
4
5
6
7
8
tBu
tBu
tBu
tBu
tBu
tBu
Ph
CO2Me
CO2Me
CO2Et
CO2Me
NO2
A
A
A
A
A
A
33 (1:0)
46 (2.7:1)
7 (1:0)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
49 (1:0)
nr
CN
11 (7.2:2:1)
nr
32 (2.4:2.4:1:1)
77c (2.9:1)
CONH2
CONEt2
SO2Ph
COPh
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
B (90 min)
B (5 min)
B (5 min)
B (5 min)
B (90 min)
B (240 min)
B (60 min)
B (5 min)
B (50 min)
B (180 min)
A
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
9
40 (1:1)
d
10
11
12
13
14
15
16
17
49 (2.7:1)
42 (1:0)
56 (4.9:1)
67 (2:1)
40 (1:0)
50 (2.3:1)
tBu
4-CF3C6H4
4-MeOC6H4
2-furyl
Me
Me
24 (1:0)
a Method used. A ) sealed tube, PhH, 200 °C, 3 h; B ) microwave reactor, PhCH3, 180 °C, time in parentheses required to achieve complete conversion
of acyl polysilane. b Figures in parentheses refer to diastereoselectivity as determined by 1H NMR or GC-MS analysis of crude reaction mixture. c Product
unstable. d [4 + 2] cycloaddition product 12 isolated in 86% ds (2.5:1.5:1); see Scheme 4.
entries 7-16). In all, cases the cyclopropane was the only
isolable product, with no evidence for silacyclobutane being
detected in the crude reaction mixture. At this stage, we had
developed a simple, neutral synthesis of silylated cyclopro-
panes from cinnamate esters and various related analogues,
and it was of interest to explore how these could be
elaborated in a synthetically useful manner. We anticipated
that Fleming-Tamao oxidation of the silyl group would
provide 2-hydroxycyclopropane carboxylates that resemble
the donor-acceptor cyclopropanes elegantly exploited by
Reissig and others.11 Despite the presence of the siloxy
group, initial attempts to directly oxidize the C-Si bond
using the classic Tamao conditions (H2O2, KF, KHCO3)
failed.12 In such situations it can be beneficial to convert
the silane precursors to the analogous fluorosilane. Following
the precedents from our earlier studies,8 siloxysilylcyclo-
propane 13a was treated with BF3·2AcOH to afford, after
30 min at room temperature, the fluorosilane 14a (Scheme
5). Surprisingly, this too was resistant to oxidation with
hydrogen peroxide. However, enhancing the reactivity of the
silicon center by conversion to the difluorosilane 15 through
prolonged treatment with BF3·2AcOH overcame this prob-
lem. The subsequent Tamao oxidation now proceeded
smoothly to afford a mixture of ketoester 17a and associated
acid, presumably arising from opening of the intermediate
Scheme 3. Thermal Rearrangement of Silacyclobutane 6
Scheme 4. Reaction of Acylpolysilane 10 with Chalcone
and short times (30 min) good yields could be obtained using
only 1 equiv of the silenophile, the high pressures generated
in the tube made it practically difficult to translate this
observation to other substrates. However, the use of micro-
wave heating at slightly lower temperatures addressed this
issue, and using this somewhat operationally simpler pro-
tocol, we then explored a selection of different polysilanes
using methyl cinnamate as a model silenophile, (Table 1
(11) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599–7662. Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. Reissig, H. U.;
Zimmer, R. Chem. ReV. 2003, 103, 1151–1196.
(12) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694–1696.
2746
Org. Lett., Vol. 11, No. 13, 2009

Scheme 5
.
Oxidative Elaboration of Silylcyclopropanes
Table 2. Oxidation of Silylcyclopropanes 13
entry 13
R1
R2
yield 14 (%) yield 17(%)
1
2
3
4
5
6
7
a
b
c
d
e
f
Ph
Me
tBu
OMe
OMe
OMe
96
94
97
98
98
56
50
61
51
45
78
22
4-MeOC6H4 OMe
4-CF3C6H4
2-furyl
OMe
OMe
61
a
g
4-MeOC6H4 NEt2
a Fluorosilane 14g was not stable to silica gel and was used directly in
the oxidation without purification.
Overall, this two-step sequence, involving silene generation
and “cycloaddition”, followed by oxidative cleavage of the
cyclopropyl ring, represents the product of the formal
addition of an acyl anion to the cinnamate group. In
conclusion, acyl polysilanes represent a new acyl anion
equivalent and in particular one that reacts under nonbasic
conditions. These results continue to demonstrate that the
unusual chemistry exhibited by silenes offers new prospects
for synthetic methodology. Further explorations of their
chemistry, together with mechanistic studies to underpin
these observations, are in progress and will be reported in
due course.
hydroxycyclopropane under the reaction conditions and
concomitant ester hydrolysis. Disappointingly, attempts to
extend this protocol to other silyl cyclopropanes resulted in
only low yields of the intermediate difluorosilane ac-
companied by extensive decomposition. Consequently we
explored different methods for the oxidation and ultimately
found that, following the precedent established by Tamao,13
the monofluorosilane could be oxidized, albeit slowly, using
mCPBA in DMF. Following further optimization, it was
found that the addition of KF to this oxidation provided both
enhanced yields and shorter reaction times. Pleasingly, this
two-step procedure proved to be applicable to all of the other
silylcyclopropanes to provide the corresponding 1,4- dicar-
bonyl compounds in reasonable yields (Table 2).
Presumably the ring opening of the cyclopropane proceeds
via the intermediate enolate anion 18, but to date, all attempts
to trap this with a variety of electrophiles have proven
unsuccessful. Practically, the process can be simplified into
a one-pot conversion with the intermediate fluorosilyl cy-
clopropane being used directly in the subsequent oxidation.
Acknowledgment. We thank the EPSRC (DTA student-
ship to M.C.) and AstraZeneca for financial support of this
work (CASE award to M.C.), the EPSRC Mass Spectrometry
Service for accurate mass determinations, Dr. A. M. Ken-
wright (University of Durham) for assistance with NMR
experiments, and Dr. M. Jones (University of Durham) for
mass spectra.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new products. This
information is available free of charge via the Internet at
http://pubs.acs.org.
(13) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.;
Yoshida, J.; Kumada, M. Tetrahedron 1983, 39, 983–990.
OL900813Z
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