Copper(II)-catalyzed silyl conjugate addition to α,β-unsaturated conjugated compounds: Bronsted base-assisted activation of Si-b bond in water

Article abstract of DOI:10.1021/ol300618j

A mild method for the installation of the dimethylphenylsilyl group on the β-carbon of electron-deficient olefins is reported. In the presence of a catalytic amount of copper(II) (1 mol %) and amine base (5 mol %) at rt, the transformation proceeds effici

Full text of DOI:10.1021/ol300618j

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2090–2093
Copper(II)-Catalyzed Silyl Conjugate
Addition to r,β-Unsaturated Conjugated
Compounds: Brønsted Base-Assisted
Activation of SiÀB Bond in Water
Joseph A. Calderone and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
santosw@vt.edu
Received March 11, 2012
ABSTRACT
A mild method for the installation of the dimethylphenylsilyl group on the β-carbon of electron-deficient olefins is reported. In the presence of a
catalytic amount of copper(II) (1 mol %) and amine base (5 mol %) at rt, the transformation proceeds efficiently in water within 1.5À5 h to afford
β-silylated products in yields of up to 90%.
The development of methods for the preparation of
organosilicon compounds is important because of their
utility as intermediates in the synthesis of complex mole-
cules as well as their potential application in material
science and medicine.1 Initial reports for the preparation
of β-silyl carbonyl compounds involved conjugate addi-
tion using stoichiometric amounts of silyl metal reagents
such as silyllithiums, silylcuprates, or silylzincates.2 How-
ever, methods that utilized catalytic amount of copper in
the presence of silylzincates have been reported.3 Alter-
native methods that utilize catalytic amounts of transition
metals have become state-of-the-art.4 Activation of the
Figure 1. β-Silylation: nucleophilic silicon from SiÀX bond.
SiÀX bond (wherein X = Si or B) in the presence of a
transition metal can provide access to siliconÀcarbon
bonds (Figure 1).5 Although disilanes are powerful sources
(1) (a) Sieburth, S. M.; Chen, C.-A. Eur. J. Org. Chem. 2006, 2006,
311. (b) Sieburth, S. M.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew.
Chem., Int. Ed. 1998, 37, 812. (c) Mutahi, M. w.; Nittoli, T.; Guo, L.;
Sieburth, S. M. J. Am. Chem. Soc. 2002, 124, 7363.
of nucleophilic silicon, recent attention has focused on
exploiting the unique reactivity of Suginome’s dimethyl-
phenylsilylpinacolatoboron (1)4a,6 as a means to transfer
(2) (a) Fleming, I.; Lee, D. J. Chem. Soc., Perkin Trans. 1 1998, 2701.
(b) Still, W. C. J. Org. Chem. 1976, 41, 3063. (c) Fleming, I.; Lee, D.
Tetrahedron Lett. 1996, 37, 6929. (d) Dambacher, J.; Bergdahl, M.
Chem. Commun. 2003, 144. (e) Auer, G.; Weiner, B.; Oestreich, M.
Synthesis 2006, 2006, 2113.
(3) (a) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem.
Soc. 1998, 120, 4021. (b) Oestreich, M.; Weiner, B. Synlett 2004, 2004,
2139–2142.
(5) (a) Ohmura, T.; Suginome, M. Bull. Chem. Soc. Jpn. 2009, 82, 29.
(b) Clark, C. T.; Lake, J. F.; Scheidt, K. A. J. Am. Chem. Soc. 2003, 126,
84. (c) Ogoshi, S.; Tomiyasu, S.; Morita, M.; Kurosawa, H. J. Am.
Chem. Soc. 2002, 124, 11598. (d) Hayashi, T.; Matsumoto, Y.; Ito, Y.
J. Am. Chem. Soc. 1988, 110, 5579. (e) Ito, H.; Ishizuka, T.; Tateiwa,
J.-i.; Sonoda, M.; Hosomi, A. J. Am. Chem. Soc. 1998, 120, 11196.
(6) For review, see Suginome, M.; Matsuda, T.; Ito, Y. Organometallics
2000, 19, 4647.
(4) (a) Weickgenannt, A.; Oestreich, M. Chem.;Eur. J. 2010, 16, 402.
(b) Hartmann, E.; Vyas, D. J.; Oestreich, M. Chem. Commun. 2011, 47, 7917.
r
10.1021/ol300618j
Published on Web 04/11/2012
2012 American Chemical Society

Table 1. Screening of Base Additivesa
Table 2. β-Silylation of R,β-Unsaturated Ketones and Estersa
Cu
mol % Prod:SM
entry
base
source
Cu
ratiob
1
potassium acetate
CuSO4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
3:1
2
potassium bicarbonate CuSO4
5:1
3
pyridine
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
none
15:1
28:1
22:1
22:1
NRd
13:1
10:1
24:1
NRd
trace
trace
13:1
21:1
26:1
4
4-picoline
2,6-lutidine
6-methylquinoline
bipyridine
DBUc
5
6
7
8
9
triethyl amine
benzylamine
none
10
11
12
13
14
15
16
none
CuSO4
none
1.0
0
4-picoline
4-picoline
4-picoline
4-picoline
CuCl
1.0
1.0
1.0
Cu(OAc)2
Cu(BF4)2
a General procedure: Amine or base (5 mol %), cyclohexen-2-one
(1 equiv), 2 (1.2 equiv), and 1 mL of 1.3 mg/mL of CuSO4 solution were
mixed at rt for 30 min. b Determined by GCÀMS of crude material. c 1,8-
Diazabicyclo[5.4.0]undec-7-ene. d NR = no reaction.
the dimethylphenylsilyl moiety to R,β-unsaturated carbo-
nyl compounds. While Rh(I)-catalyzed methods have been
reported,7 copper(I)-catalysis is emerging as a more con-
venient and efficient protocol.8 Indeed, a few enantio-
selective methods7a,c are available as well as a metal-free9
variant catalyzed by N-heterocyclic carbenes (NHC).
An analogous reaction is the β-borylation of R,β-un-
saturated carbonyl compounds catalyzed by copper.10 In
this reaction,11 transfer of the boron moiety from diboron
a General procedure: Amine (5 mol %), substrate (1 equiv),
2 (1.2 equiv), and 1 mL of 1.3 mg/mL of CuSO4 solution were mixed
at rt until the reaction was complete as determined by TLC. b Isolated
yield. c NMR yield: 83%.
(7) (a) Hartmann, E.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49,
6195. (b) Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed.
2006, 45, 5675. (c) Walter, C.; Oestreich, M. Angew. Chem., Int. Ed. 2008,
€
47, 3818. (d) Walter, C.; Frohlich, R.; Oestreich, M. Tetrahedron 2009,
65, 5513.
(8) (a) Lee, K. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898.
(b) Welle, A.; Petrignet, J.; Tinant, B.; Wouters, J.; Riant, O. Chem.;
reagents such as bis(pinacolato)diboron or tetrahydroxy-
diborane12 is initiated by activating Lewis bases.13 Con-
sistent withourongoing interestwithLewis base activation
of boron, we recently disclosed an improved protocol that
utilizes catalytic amounts of CuII and amine run at rt, open-
to-air, and uses water as the solvent medium.14 A suggested
mechanism proposes that the amine serves two roles: (1) as
ꢀ
Eur. J. 2010, 16, 10980. (c) Ibrahem, I.; Santoro, S.; Himo, F.; Cordova,
A. Adv. Synth. Catal. 2011, 353, 245.
(9) O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133,
7712.
€
(10) (a) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem.,
Int. Ed. 2010, 49, 1194. (b) Bonet, A.; Sole, C.; Gulyas, H.; Fernandez, E.
Curr. Org. Chem. 2010, 2, 501. (c) Mantilli, L.; Mazet, C. ChemCatChem
2010, 2, 501.
(11) (a) Lee, J. E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145. (b)
ꢀ
Lillo, V.; Prieto, A.; Bonet, A.; Dıaz-Requejo, M. M.; Ramırez, J.; Perez,
´ ´
(12) Molander, G. A.; McKee, S. A. Org. Lett. 2011, 13, 4684.
(13) (a) Gao, M.; Thorpe, S. B.; Santos, W. L. Org. Lett. 2009, 11,
3478. (b) Thorpe, S. B.; Guo, X.; Santos, W. L. Chem. Commun. 2011,
47, 424. (c) Gao, M.; Thorpe, S. B.; Kleeberg, C.; Slebodnick, C.;
Marder, T. B.; Santos, W. L. J. Org. Chem. 2011, 76, 3997. (d) Pubill-
Ulldemolins, C.; Bonet, A.; Bo, C.; Gulyas, H.; Fernandez, E. Chem.;
Eur. J. 2012, 18, 1121.
(14) Thorpe, S. B.; Calderone, J. A.; Santos, W. L. Org. Lett. 2012,
14, 1918.
ꢀ
P. J.; Fernandez, E. Organometallics 2008, 28, 659. (c) Chen, I. H.; Yin,
L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664. (d) Lillo, V.; Bonet, A.; Fernandez, E. Dalton Trans. 2009, 2899.
(e) Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 7253. (f) Bonet, A.; Gulyas, H.; Fernandez, E. Angew. Chem., Int.
Ed. 2010, 49, 5130. (g) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A.
Tetrahedron Lett. 2000, 41, 6821. (h) Takahashi, K.; Takagi, J.; Ishiya-
ma, T.; Miyaura, N. Chem. Lett. 2000, 29, 126. (i) Takahashi, K.;
Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 625, 47.
ꢀ
ꢀ
Org. Lett., Vol. 14, No. 8, 2012
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Table 3. β-Silylation of Other R,β-Unsaturated Conjugated
Scheme 1. Proposed Catalytic Cycle
Compoundsa
ligand such as bipyridine was ineffective (entry 7), which is
consistent with our previous observations.13 On the other
hand, alkyl amines could also affect the conversion to 3a
(entries 8À10). Control reactions showed that both copper
and amine are required in the reaction (entries 11À13).
Further, it was confirmed that Cu(II) sources are superior
catalysts than Cu(I) (compare entries 14 vs 15À16).16
With the optimum conditions determined (Table 1,
entry 4), we explored the suitability of a variety of R,β-
unsaturated conjugated compounds for silyl conjugate
addition (Table 2). Cyclic ketones 2a,b underwent
β-silylation in good to excellent yields (entries 1À2).
Acyclic ketones were also good substrates. For example,
ketones bearing alkyl or aryl substitutent on the β-carbon
were converted to the desired products 3cÀe in 68À84%
yield (entries 3À5). Further, a regioselective 1,4-addition
occurred with a R,β,γ,δ-unsaturated substrate 2f, afford-
ing 3f in excellent yield (entry 6). This result is surprising
because Hoveyda observed 1,6-addition using a CuIÀ
NHC protocol.8a Hence, our method nicely complements
the CuIÀNHC protocol that affords the alternative 1,4-
addition product. Indeed, we were delighted to demon-
strate that electronically more demanding and sterically
encumbered R,β-unsaturated esters are suitable as sub-
strates. To date, only a handful of examples of esters as
substrates have been reported.7b,8 Thus, the efficient trans-
formation of 2gÀ2j containing either a methyl or phenyl
substituent on the R or β position to 3gÀ3j demonstrates
the utility of the developed reaction method (entries 7À10).
To further investigate the generality of the substrate
scope of the reaction, substrates 4aÀe were subjected to the
reaction conditions (Table 3). Although R,β-unsaturated
aldehydes can suffer from competing 1,2- or 1,4-silyl
conjugate addition, to our delight, 4a,b were transformed
to 5a,b in good yields (entries 1À2). Acrylonitrile was also
effectively silylated (5c) in 44% yield. A clear limitation of
the reaction is with the less electrophilic R,β-unsaturated
diethylvinylphosphonate 4d, wherein no product was ob-
served even under slightly elevated temperature. However,
a General procedure: Amine (5 mol %), substrate (1 equiv), 2
(1.2 equiv), and 1 mL of 1.3 mg/mL of CuSO4 solution were mixed at
rt until the reaction was complete as determined by TLC. b Reaction was
heated at 50 °C. c NR = no reaction
a ligand for copper and (2) as a Bronsted base for the
activation of a nucleophilic water molecule. We surmised
that the same catalyst system would facilitate silyl con-
jugate addition to R,β-unsaturated carbonyl compounds.
With such a procedurally simple protocol, silyl conjugate
additions could be performed open-to-air using water as
the solvent. Additionally, use of an inexpensive CuII source
(i.e., CuSO4) is advantageous because it is insensitive to
moisture and resistant to oxidation upon exposure to air.
Further, Lewis base additives that hydrolyze in the pre-
sence of adventitious water such as KOtBu or DBU/
NHC15 can be substituted with inexpensive amines com-
monly found in most laboratories. In this report, we
disclose our efforts toward achieving such a protocol.
To determine the optimal conditions of the reaction, we
treated cyclohexanone (2a) with 1 in the presence of a
catalytic amount of copper catalyst and screened several
amines as well as potassium acetate and potassium bicar-
bonate (Table 1). Although some conversion of 2a to 3a
was observed with potassium acetate and potassium car-
bonate (entries 1À2), we found that amines that can form
coordination complexes providing the desired product in
much better conversions. For example, aromatic amines
resulted in consistently high conversions with 4-picoline
performing the best (entries 3À6). However, a bidentate
(16) We suspect that the active catalyst in the presence of CuCl is
Cu(II), which is formed by the disproportionation of Cu(I) to Cu(II) and
Cu(0) in water. For a detailed discussion, see ref 14.
(15) NHCs have been suggested to undergo decomposition under
aqueous conditions; see ref 9.
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Org. Lett., Vol. 14, No. 8, 2012

installation of the silyl group on the β-carbon of a more
reactive phenylvinylsulfone 4e proceeded in good yield
(entry 5). To the best of our knowledge, this is the
first report of a conjugative silylation that furnishes a
β-silylsulfone.
A proposed catalytic cycle is illustrated in Scheme 1. We
suspect that the role of the amine is to deprotonate a
nucleophilic water molecule in a manner analogous to the
activation of a diboron13 to form an sp3-hybridized boro-
nate (6), which in turn activates the SiÀB bond. In the
presence of a CuII complex, transmetalation can occur to
produce CuIIÀSi complex 7. The resulting nucleophilic Si
undergoes either a 1,4- or 3,4-addition reaction (only 3,4-
addition is shown) with R,β-unsaturated carbonyl sub-
strate to afford intermediate 8; protonation by water leads
to the desired product 9 and CuII-complex catalyst, com-
pleting the cycle.
addition of R,β-unsaturated conjugated compounds. The
method is highly tolerant of many electron withdrawing
groups on the alkene substrate. The presence of catalytic
amounts of amine base and copper allows for the protocol
to be performed at rt, open-to-air, and with water as the
solvent to provide β-silylated products in good to excellent
yields. Further extension and application of the method is
currently underway.
Acknowledgment. Financial support was provided by
the ACS Petroleum Research Fund and the Chemistry
Department at Virginia Tech. We thank S. Brandon
Thorpe, Mithun Raje, and David Bryson from Virginia
Tech for their critical reading of this manuscript.
Supporting Information Available. Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we disclose, to the best of our knowledge,
the first Cu(II)-catalyzed protocol for the silyl conjugate
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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