Copper(I)-Catalyzed Disilylation of Alkylidene Malonates Employing a Lewis Base Activation Strategy

Article abstract of DOI:10.1021/ja038530t

The disilylation of activated α,α-unsaturated esters has been accomplished by utilizing symmetrical disilanes and catalytic quantities of copper(I) salts in the presence of Lewis bases such as DMF. This new methodology with various alkylidene malonates is

Full text of DOI:10.1021/ja038530t

Published on Web 12/16/2003
Copper(I)-Catalyzed Disilylation of Alkylidene Malonates Employing a Lewis
Base Activation Strategy
Christopher T. Clark, Jason F. Lake, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
Received September 15, 2003; E-mail: scheidt@northwestern.edu
Table 1. Effect of Solvent and Catalysts on the Catalytic
Disilylation of Alkylidene Malonates 1aa
The efficient incorporation of silicon into organic molecules
provides important access to organosilicon compounds with sig-
nificant utility in organic synthesis.1 Of the many reactions that
accomplish this goal, the conjugate addition of silyl nucleophiles
to unsaturated systems is a particularly powerful method for the
synthesis of functionalized â-silyl carbonyl compounds. Established
approaches for this reaction manifold typically involve stoichio-
metric additions of anionic silyl nucleophiles.2 However, an alternate
strategy for the overall conjugate addition of silyl groups involves
metal-catalyzed disilylations of R,â-unsaturated ketones.3 Although
methods exist that employ this approach, the potentially more useful
and general strategy for the disilylation of R,â-unsaturated esters
remains an unsolved challenge. In this communication, we report
the copper(I)-catalyzed disilylation of alkylidene malonates (1) with
disilanes (2) in the presence of Lewis bases to yield functionalized
â-silyl diesters (3, eq 1).
entry
catalyst
CuI
mol%
solvent
DMFf
conversiond (%)
yield (%)e
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
5
16
16
4
5
CuCN
CuPF6
DMF
DMF
b
65
54
56
42
31
28
-
[CuOTf]c
[CuOTf]
[CuOTf]
[CuOTf]
[CuOTf]
[CuOTf]
[CuOTf]
DMF
84
75
67
62
0
>95
28
DMIg
NMPh
HMPAi
toluene
DMF/toluenej
DMF/toluene
48
21
2.5
a All reactions are heated at 100 °C for 60 h then quenched with TsOH
and H2O. b CuPF6(CH3CN)4. c [(CuOTf)2‚benzene]. d Conversion based on
1H NMR (500 MHz) spectroscopy. e Isolated yield after chromatography.
f Dimethylformamide. g 1,3-Dimethyl-2-imidazolidinone. h N-Methyl-2-pyr-
rolidinone. i Hexamethylphosphoramide. j 10 equiv of DMF in toluene.
Table 2. Impact of Ligand on Efficiency of Catalytic Disilylationa
The activation of disilanes to generate silyl anions is a well-
known process.4 Recently, it has been demonstrated that the addition
of Lewis bases such as 1,3-dimethyl-2-imidazolidinone (DMI) and
dimethylformamide (DMF) activate Si-Si bonds for disilylations
of unsaturated organic molecules.5 With this in mind, it was felt
that coupling this activation strategy with the use of R,â-unsaturated
esters as substrates and readily available disilanes should afford a
metal-catalyzed disilylation reaction that would generate highly
useful â-silyl esters.
Our initial survey of potential activated unsaturated esters for
the desired metal-catalyzed disilyation revealed that the combination
of alkylidene malonates (1) with commercially available diphen-
yltetramethyldisilane (2a), copper(I) triflate (10 mol %) and tri-n-
butylphosphine (20 mol %) in DMF gratifyingly afforded the
desired â-silyl diester 3a in moderate yield after in situ hydrolysis
(Table 1, eq 2). An investigation of copper(I) sources indicated
that, while multiple salts affected the desired reaction, copper(I)
triflate was the optimal catalysts in terms of conversion and yield
(entries 1-4).6 Employing Lewis bases such as DMF, DMI, NMP,
and HMPA (entries 4-7) were crucial for good levels of conversion,
with DMF providing the greatest isolated yield (56%). While
modulating the Lewis base component of the reaction has a
relatively minimal impact on the process, the absence of such
functionality affords no reaction (entry 8). In the cases where
toluene is utilized as solvent and DMF is an additive (10 equiv),
the reaction proceeds to complete conversion, even at catalyst
loadings as low as 5 mol % (entry 9).7
c
entry
ligand
none
n-Bu3P
n-Bu3P
P(OPh)3
P(OEt)3
pyridine
pyridine
R
DMF (equiv)
conversion (%)
yield (%)
1
2
3
4
5
6
7
Ph (2a)
Ph
10
1
60
0
>95
75
>95
>95
70
32
0
Ph
Ph
Ph
Ph
10
10
10
10
10
48
45
52
67
35
vinyl (2b)
a All reactions were heated at 100 °C for 60 h (0.5 M in substrate).
b [(CuOTf)2‚benzene]. c Conversion based on 1H NMR (500 MHz) spec-
troscopy.
proceeds, albeit in lower yield (32%, entry 1). Interestingly,
increasing the concentration of n-Bu3P to 40 mol % (4 equiv relative
to CuOTf) or utilizing other phosphines affords no product.8
However, the use of phosphites (entries 4, 5), promotes the reaction
up to 52% yield. In an effort to utilize more convenient ligands,
pyridine was employed. Gratifyingly, the reaction proceeds to
complete conversion in 67% yield (entry 6). The structure of the
disilane also significantly impacts the outcome of the reaction. For
example, although 1,2-disubstituted tetramethyldisilanes (diphenyl,
divinyl) cleanly afford â-silyl diesters with 10 mol % [CuOTf], 20
mol % pyridine, and 10 equiv of DMF in toluene (entries 6, 7)
after hydrolysis, the use of more hindered disilanes does not provide
desired product.9
With the optimal copper(I) catalyst and solvent mixture identified,
the effects of ligand and disilane structure on the reaction were
evaluated (Table 2). In the absence of n-Bu3P, the reaction still
9
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J. AM. CHEM. SOC. 2004, 126, 84-85
10.1021/ja038530t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Disilylation of Various Alkylidene Malonates (1)a
yield. Further investigations into the mechanism of this reaction
and the development of asymmetric variants of this process are
currently under way and will be reported in due course.
yield
(%)
yield
(%)
entry
R
product
entry
R
product
1
2
3
4
5
6
7
Ph
Cl-Ph
4-F-Ph
4-NO2Ph
2-furyl
67
87
53
0
80
67
64
3a
4
5
6
7
8
9
1-napthyl
2-napthyl
n-pentyl
(CH2)2Ph
Me
84
10
11
12
13
14
15
16
Acknowledgment. This work has been supported by North-
western University. J.F.L. thanks Northwestern for an Undergradu-
ate Summer Research Grant. We thank Wacker Biochem Co.
(Specialties Division, Adrian, MI) for kindly supplying organosili-
con reagents and Professor Thomas Meade and Alisha Taylor (NU)
for assistance with shared instrumentation.
84
10
11
12
13
14
60c
37c
40c
4-MeOPh
2-MeOPh
8
9
NHCOCF3 57
CO2Et
d
-
a All reactions were heated at 100 °C for 24-60 h. Reported yields are
after chromatographic purification. b [(CuOTf)2‚benzene]. c 15 mol % [CuOTf],
30 mol % pyridine. d Product de-silylates upon hydrolysis.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Once the best conditions had been identified, the scope of the
reaction was explored (eq 3, Table 3). With aryl alkylidene
malonates, our reaction generates â-silyl diesters in good yield. It
is tolerant of both electron-rich and electron-poor aromatic rings.
However, the incorporation of a nitro group (entry 4) surprisingly
affords no desired product.10 With slightly higher catalyst loadings,
reactions employing alkyl alkylidene malonates generate â-silyl
diesters in moderate yields (entries 10-12).11 Notably, a â-silyl-
â-amino ester can be generated in moderate yield when â-trifluo-
roacetamido alkylidene malonate is utilized as a substrate (entry
13, 57% yield).12
A plausible catalytic cycle for this reaction is depicted in Scheme
1. Interaction between the Lewis base (DMF) and the disilane
produces an activated electron-rich silicon species that undergoes
transmetalation to copper(I) triflate. The nucleophilic activation of
organosilanes has been observed by 29Si NMR.13 The copper
intermediate I undergoes conjugate addition to alkylidene malonate
(2), and the resulting copper enolate II is trapped by the silyl triflate/
silyl Lewis base adduct, thus regenerating the copper(I) catalyst.
Pyridine presumably acts as a ligand for copper throughout the
catalytic cycle.
References
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Verlag: Berlin, 1983. (b) Colvin, E. W. Silicon Reagents in Organic
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A.; Walter, D. Chem. ReV. 1997, 97, 2063-2192.
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J. Chem. Soc., Perkin Trans. 1 1981, 2520-2526. (c) Crump, R. A. N.
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Organocopper Reagents: A Practical Approach; Oxford University
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Lichtenwalter, G. D. J. Am. Chem. Soc. 1958, 80, 608-611. For reviews
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1995, 95, 1351-1374. (f) Horn, K. A. Chem. ReV. 1995, 95, 1317-1350.
(g) Suginome, M.; Ito, Y. Chem. ReV. 2000, 100, 3221-3256.
(5) Ito, H.; Ishizuka, T.; Tateiwa, J.; Sonoda, M.; Hosomi, A. J. Am. Chem.
Soc. 1998, 120, 11196-11197.
(6) (a) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 1889-
1897. (b) Cohen, T.; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J.
R. Organic Syntheses; John Wiley & Sons: New York; Collect. Vol. 6,
pp 737-743. Omission of [CuOTf] results in no reaction.
(7) Yields for 3a are substantially lower than conversion would indicate. See
Supporting Information for details regarding this observation.
(8) Phosphines such as (t-Bu)3P, Cy3P, Ph3P, and 2-di-(tert-butylphosphino)-
biphenyl give no conversion.
Scheme 1. Proposed Catalytic Cycle for Disilyation Reaction
(9) Hexaphenyldisilane and tetraphenyldimethyldisilane afford no product.
(10) The deleterious effect of nitro groups on [CuOTf]-catalyzed reactions has
been observed: Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt,
K. A. Org. Lett. 2003, 5, 3487-3490.
(11) This is primarily due to the instability of the starting material at elevated
reaction temperatures.
(12) For the only other report of a simple R-silyl-R-amino ester, see: Fleming,
I.; Marangon, E.; Roni, C.; Russell, M. G.; Chamudis, S. T. Chem.
Commun. 2003, 200-201.
The synthetic utility of our â-silyl diester products is highlighted
in eq 5. The decarboxylation of 3a followed by a highly diaste-
reoselective alkylation (dr g 20:1) affords R-substituted-â-silyl ester
17 in 62% for the two steps.14 A straightforward oxidation produces
â-hydroxy ester 18 in excellent yield (89%) without elimination.15
In conclusion, a copper(I)-catalyzed disilylation of alkylidene
malonates has been described. The reaction is broad in scope,
utilizes commercially available disilanes and ligands, and provides
a new catalytic route to synthetically useful â-silyl diesters in good
(13) Organosilanes in the presence of Lewis bases generate highly electron
rich silyl species: Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res.
2000, 33, 432-440 and references therein. The 29Si NMR spectrum of
(Me2PhSi)2 with 10 equiv of DMF (toluene-d8) has a distinct broad peak
at -117 ppm. The 29Si NMR signal of (Me2Ph)2Si (toluene-d8) is -19
ppm.
(14) Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. J. Org. Chem. 1991, 56, 7341-
7344 and references therein.
(15) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J.
J. Chem. Soc., Perkin Trans. 1 1995, 317-337.
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