Copper-free and copper-promoted conjugate addition reactions of bis(triorganosilyl) zincs and tris(triorganosilyl) zincates

Article abstract of DOI:10.1055/s-2006-942405

In the course of our investigations directed towards an asymmetric copper-catalyzed silyl transfer from bis(triorganosilyl) zincs onto α,β-unsaturated carbonyl compounds, the presence of Lewis acidic lithium cations and the uncatalyzed background reaction

Full text of DOI:10.1055/s-2006-942405

PAPER
2113
Copper-Free and Copper-Promoted Conjugate Addition Reactions of
Bis(triorganosilyl) Zincs and Tris(triorganosilyl) Zincates
C
G
opper-Free and
C
e
opper-Prom
r
oted
C
t
r
e
Additi
u
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
Fax +49(761)2036100; E-mail: martin.oestreich@orgmail.chemie.uni-freiburg.de
Received 30 March 2006
Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday
ants are still elusive and, to date, an enantioselective, pal-
Abstract: In the course of our investigations directed towards an
asymmetric copper-catalyzed silyl transfer from bis(triorganosilyl)
zincs onto a,b-unsaturated carbonyl compounds, the presence of
12
ladium-catalyzed 1,4-bissilylation of a,b-unsaturated
ketones remains the sole example.13 In this paper, we
8
Lewis acidic lithium cations and the uncatalyzed background reac- present an attempt to perform our recently reported cop-
tion were identified as major causes thwarting appreciable enantio- per-catalyzed silylzincation of a,b-unsaturated carbonyl
selection. The latter finding underlines once more that copper is
compounds enantioselectively. Within this investigation,
often not even required in the conjugate addition of bis(triorgano-
silyl) zincs and tris(triorganosilyl) zincates alike.
we learned that bis(triorganosilyl) zincs cleanly react with
virtually all standard acceptors in the absence of a copper8
Key words: catalysis, cuprates, silicon, zinc, copper
catalyst. A comparison of the known copper-catalyzed
and the novel copper-free process is provided.
We reasoned that our reagent–copper catalyst combina-
In synthetic organic chemistry, silicon attached to saturat-
ed carbon serves either as a masked hydroxyl group or as
8
tion, (R Si) Zn/Cu(OTf) (5.0 mol%), is comparable to
3
2
2
R Zn/Cu(OTf) that has been successfully employed in
2
2
1
a linchpin for carbon–carbon bond-forming reactions.
the copper-catalyzed enantioselective conjugate addition
2
Importantly, both oxidative degradation and palladium-
14
of diorganozincs. Consequently, we adopted these es-
3
catalyzed cross-coupling of the carbon–silicon bond pro-
tablished reaction conditions and simply replaced Et Zn
2
ceed with immaculate retention of the configuration at the
silicon-bearing carbon, thereby qualifying this functional
group for stereoselective synthesis.
15
by (Me PhSi) Zn (1 → 2, Scheme 1). As exemplified by
a selected experiment, adduct 2 was invariably formed as
2
2
a racemic mixture in the presence of phosphoramidite-
Among the numerous methods available today, the conju- based ligand L.
gate addition of silicon–metal reagents is still one of the
4
main carbon–silicon bond-forming reactions. Classical
cuprates such as (R Si) CuLi·LiCN as well as
Cu(OTf)2 (5.0 mol%)
L (10 mol%)
Me2PhSi)2Zn (1.0 equiv)
O
O
3
2
(
i-Pr
i-Pr
5
O
O
R SiCu·LiCN and, more recently, R SiCu·LiI stabilized
by Me S were introduced and utilized with considerable
success. Whereas these reagents rely on stoichiometric
amounts of copper, several procedures requiring copper as
P N
3
3
Me
Me
6
THF–Et O–PhMe = 10:2:5
*
2
2
Si
Ph
2: 0% ee
–
20 °C
9
0%
1
L
catalyst are also available: cuprate-catalyzed 1,4-addition
Scheme 1 Attempted asymmetric copper-catalyzed conjugate addi-
tion
7
of mixed zincates [Me CuLi·LiCN (3.0 mol%)/
2
(
R Si)Me ZnLi], copper-catalyzed 1,4-addition of bis(tri-
3 2
8
organosilyl) zincs [CuCN (5.0 mol%)/(R Si) Zn], and
3
2
formal copper-catalyzed 1,4-addition of disilanes9
(CuOTf) ·PhH (5.0 mol%)/R SiSiR ]. The conjugate si-
In the mechanism proposed for the copper-catalyzed 1,4-
addition of R Zn, high p-face selectivity is attributed to a
2
[
2
3
3
conformationally rigid bimetallic complex of the enone
moiety and the zinc reagent–copper catalyst couple with a
lyl transfer from (mixed) zincates proceeds even in the ab-
1
0
sence of a copper catalyst.
14
ligand-to-copper ratio L/Cu(I) = 2:1. By analogy, the re-
lated desired chelate in our catalysis might be depicted as
A (Figure 1).
In light of the synthetic relevance of silicon attached to
stereogenic carbon (vide supra), stereoselective carbon–
silicon bond formation by means of copper-mediated con-
jugate addition of silicon nucleophiles to a,b-unsaturated
carbonyl compounds is a worthwhile objective. For this,
some diastereoselective, chiral-auxiliary-based methods
Cl
SiMe2Ph
Zn
LiCl
O
O
SiMe Ph
2
1
1
2
SiMe Ph
were developed. Conversely, catalytic asymmetric vari-
Cu
Cu
L
L
L
L
A
B
SYNTHESIS 2006, No. 13, pp 2113–2116
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.06.2006
DOI: 10.1055/s-2006-942405; Art ID: C01006SS
Georg Thieme Verlag Stuttgart · New York
Figure 1 Mechanistic model
©

2
114
G. Auer et al.
PAPER
We believe that in our case an intermediate of type A g,g-disubstituted derivative 3 prevented the conjugate si-
might not be formed since (Me PhSi) Zn is contaminated lyl transfer from (Me PhSi) Zn and (Me PhSi) ZnLi, re-
2
2
2
2
2
3
with a four-fold excess of lithium chloride [(Me PhSi) Zn spectively at low temperature (3 → 4, Table 1, entry 2).
2
2
=
(Me PhSi) Zn·4LiCl], which is inevitably introduced in This substrate was later used in a reactivity study (vide in-
2 2
1
6
the synthesis of the zinc reagent via reductive lithiation
fra). Isophorone (5) with two substituents in the b-position
and transmetallation (top, Scheme 2). Lewis acidic lithi- emerged as completely inert towards the zinc reagents
um cations will compete with any zinc species for coordi- without a copper catalyst even at higher temperatures
nation at the Lewis basic carbonyl oxygen. The less rigid (5 → 6, Table 1, entry 3). In the end, 5 was the only enone
complex B might then be the predominant intermediate, in requiring a copper catalyst. Reaction of lactone 7 gave 8
which facial selectivity of the coordinated chiral mono- in good yield with CuCN and moderate yield without
1
7
silylcopper species is markedly diminished (Figure 1).
CuCN (7 → 8, Table 1, entry 4). Chalcone (9) (9 → 10,
Table 1, entry 5) and acyclic esters 11 and 13 (11/13 →
12/14, Table 1, entries 6 and 7) performed equally well on
applying Methods A, B, and C.
ZnCl2
4
Li
THF
°C
Me2PhSiCl
(1 M in Et2O)
(
Me2PhSi)2Zn·4LiCl
(Me2PhSi)2Zn
2
2
Me2PhSiLi·2LiCl
Me2PhSiK·2KCl
=
THF
0 °C
Since g,g-disubstituted 3 was less reactive than its parent
compound 1, we tested the effect of copper on the reaction
rate using 3 (Table 2). While 3 was completely unreactive
at –78 °C, it was cleanly converted into 4 within minutes
in the presence of CuCN (5.0 mol%) at –20 °C (Table 2,
entry 1). At the same temperature and in the absence of
CuCN, conversion was substantially slower, yet afforded
0
2
ZnCl2
(1 M in Et2O)
4
KC8
THF
°C
(Me2PhSi)2Zn·4KCl
THF
0 °C
0
Scheme 2 Contamination with lithium or potassium chloride
4
in reasonable yield (Table 2, entries 1–4). Hence, a cop-
per catalyst is not necessary for a successful conjugate si-
lylation of a variety of a,b-unsaturated carbonyl
compounds; it merely accelerates or promotes this pro-
cess.
In order to verify this hypothesis, we exchanged lithium
for less Lewis acidic potassium chloride by using the po-
tassium–graphite intercalation compound KC in the re-
8
1
8
ductive metallation step (bottom, Scheme 2). We were
pleased to find that this modification, for the first time, re-
sulted in a distinct enantiomeric excess in a copper-cat-
alyzed conjugate silyl transfer (1 → 2, Scheme 3).
Variation of the copper source (CuI or CuCN) brought no
further improvement of enantioselectivity.
In summary, we have demonstrated that a catalytic asym-
metric variant of our copper-catalyzed 1,4-addition of
bis(triorganosilyl) zincs is complicated by: 1) the pres-
ence of an excess of Lewis acidic lithium chloride and 2)
the facile uncatalyzed silyl transfer. This copper-free con-
jugate addition is general (six examples) except for b,b-
disubstituted a,b-unsaturated carbonyl compounds (one
example). Whereas in most conjugate addition reactions
1
9
2
0
Cu(OTf)2 (5.0 mol%)
L (10 mol%)
O
O
(
Me2PhSi)2Zn·4KCl (1.0 equiv)
17
and some silylzincations of alkynes copper is not need-
Me
Me
THF–Et2O–PhMe = 10:2:5
*
ed, it is essential in the related allylic substitution reac-
Si
Ph
2: 21% ee
–
20 °C
23
tion.
20%
1
Reagents obtained from commercial suppliers were used without
further purification unless otherwise noted. All reactions were per-
formed in flame-dried glassware under a static pressure of argon.
Liquids and solutions were transferred with syringes or double-end-
Scheme 3 Influence of the Lewis acidity of the counter cation
In the initial phase of the elaboration of a reliable reaction
protocol for the copper-catalyzed conjugate addition of ed needles. Solvents were dried prior to use following standard pro-
bis(triorganosilyl) zincs, we had already detected that in cedures (tetrahydrofuran, diethyl ether, and toluene). Technical
grade solvents for extraction or chromatography (cyclohexane and
some cases (Me PhSi) Zn would undergo the 1,4-addition
2
2
2
1
tert-butyl methyl ether) were distilled before use. Analytical TLC
was performed on silica gel SIL G-25 glass plates by Macherey–
Nagel (Germany) and flash chromatography on silica gel 60 (40–63
mm, 230–400 mesh, ASTM) by Merck (Germany) using the indicat-
even without a copper catalyst. If this background reac-
tion is as fast as the copper-catalyzed reaction pathway,
asymmetric induction would always be marginal. We,
therefore, returned to a careful analysis of the copper-free
1
13
ed solvents. H and C NMR spectra were recorded in CDCl on a
3
reaction of a,b-unsaturated carbonyl compounds with Bruker DRX 500 instrument. All compounds gave satisfactory ele-
mental analyses.
(
Me PhSi) Zn (Method B, Table 1). For comparison,
2 2
yields obtained for (Me PhSi) Zn in the presence of cata-
2
2
8
Copper-Free 1,4-Addition of Bis(triorganosilyl) Zinc; General
Procedure
lytic amounts of CuCN (Method A, Table 1) and for the
previously reported tris(triorganosilyl) zincate
Me PhSi) ZnLi (Method C, Table 1) are listed. Inde-
8
A freshly prepared Et O solution of (Me PhSi) Zn (2.00 mmol,
2
2
2
2
2
(
2
3
1.00 equiv) was cooled to the indicated temperature and treated with
pendent of the reaction conditions, 2-cyclohexenone (1) the a,b-unsaturated carbonyl compound (2.00 mmol, 1.00 equiv)
cleanly underwent 1,4-addition in excellent yields (1 → 2, via a syringe. The resulting reaction mixture was maintained at this
temperature for 5 h and then poured into sat. aq NH Cl (25 mL). The
Table 1, entry 1). In contrast, increased steric hindrance in
4
aqueous phase was separated and extracted with tert-butyl methyl
Synthesis 2006, No. 13, 2113–2116 © Thieme Stuttgart · New York

PAPER
Copper-Free and Copper-Promoted Conjugate Addition Reactions
2115
Table 1 Comparative Investigation of the Copper-Catalyzed Conjugate Addition of Bis(triorganosilyl) Zincs and the Copper-Free Conjugate
Addition of Bis(triorganosilyl) Zincs [(Me PhSi) Zn] as well as Tris(triorganosilyl) Zincates [(Me PhSi) ZnLi]
2
2
2
3
O
8
O
Method A (Oestreich et al.): Method B (this work):
Method C (this work):
(Me PhSi) ZnLi (1.0
Methods A−C
CuCN (5.0 mol%)
(Me PhSi) Zn (1.0 equiv)
2 2
2
3
Me
Me
(Me PhSi) Zn (1.0 equiv)
THF–Et O = 5:1
–78 °C or 0 °C
equiv)
THF–Et O = 5:1
2
2
2
Si
THF–Et O–PhMe = 10:2:5
2
2
–
20 °C
–78 °C or 0 °C
Ph
Entry
1
Substrate
Product
Yield (%) for
Method A
Temp (°C)
Yield (%) for Yield (%) for
Method B
Method C
O
O
90
90
70
70
70
80
80
-78
85
95
Me
Me
Si
1
Ph
2
2
3
4
5
6
7
O
O
-78
0
0
0
(
see Table 2)
Me
Me
Si
Me Me
Me Me
Ph
3
4
O
O
0
0
Me
Me
Me
Me
Me
Me
Me
Si
Me
Ph
5
6
O
O
O
0
40
75
70
80
-
O
Me
Me
Si
Ph
7
8
O
O
-78
-78
-78
55
70
70
Ph
Ph
Ph
Me
Me
Ph
Si
Ph
9
1
0
O
O
MeO
MeO
Me
Me
Me
Me
Si
11
Ph
1
2
O
O
EtO
EtO
Me
Me
Ph
Ph
Si
Ph
13
1
4
Synthesis 2006, No. 13, 2113–2116 © Thieme Stuttgart · New York

2
116
G. Auer et al.
PAPER
Table 2 Copper-Promoted Conjugate Addition
(5) (a) Ager, D. J.; Fleming, I. J. Chem. Soc., Chem. Commun.
1
978, 177. (b) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem.
O
O
Soc., Perkin Trans. 1 1981, 2520. (c) Fleming, I.; Newton,
T. W. J. Chem. Soc., Perkin Trans. 1 1984, 1805.
(d) Lipshutz, B. H.; Reuter, D. C.; Ellsworth, E. L. J. Org.
Chem. 1989, 54, 4975. (e) Amberg, W.; Seebach, D. Chem.
Ber. 1990, 123, 2439. (f) Tamao, K.; Kawachi, A.; Ito, Y. J.
Am. Chem. Soc. 1992, 114, 3989.
(
Me2PhSi)2Zn (1.0 equiv)
THF–Et2O = 5:1
Me
Me
Si
Ph
–20 °C
Me Me
Me Me
3
4
(
6) (a) Dambacher, J.; Bergdahl, M. Chem. Commun. 2003,
144. (b) Dambacher, J.; Bergdahl, M. J. Org. Chem. 2005,
70, 580.
Entry
Time (min)
Isolated yield (%) Yield (%)
with CuCN
without CuCN
(
7) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem.
Soc. 1998, 120, 4021.
1
2
3
4
15
30
90
90
90
90
35
60
65
75
(
(
8) Oestreich, M.; Weiner, B. Synlett 2004, 2139.
9) (a) Ito, H.; Ishizuka, T.; Tateiwa, J.-i.; Sonoda, M.; Hosomi,
A. J. Am. Chem. Soc. 1998, 120, 11196. (b) Clark, C. T.;
Lake, J. F.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 84.
60
120
(10) (a) Tückmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber.
986, 119, 1581. (b) Crump, R. A. N. C.; Fleming, I.; Urch,
C. J. J. Chem. Soc., Perkin Trans. 1 1994, 701.
c) Vaughan, A.; Singer, R. D. Tetrahedron Lett. 1995, 36,
683. (d) MacLean, B. L.; Hennigar, K. A.; Kells, K. W.;
1
(
5
ether (3 × 25 mL). The combined organic layers were back-extract-
Singer, R. D. Tetrahedron Lett. 1997, 38, 7313.
(11) (a) Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T.
Helv. Chim. Acta 1986, 69, 1542. (b) Fleming, I.; Kindon,
N. D. J. Chem. Soc., Chem. Commun. 1987, 1177.
ed with H O (25 mL) and brine (25 mL). After drying (Na SO ), the
2
2
4
solvents were evaporated under reduced pressure and the resulting
crude product was purified by flash chromatography on silica gel
using cyclohexane-tert-butyl methyl ether solvent mixtures.
(c) Palomo, C.; Aizpurua, J. M.; Iturburu, M.; Urchegui, R.
J. Org. Chem. 1994, 59, 240. (d) Hale, M. R.; Hoveyda, A.
H. J. Org. Chem. 1994, 59, 4370. (e) Fleming, I.; Kindon,
N. J. Chem. Soc., Perkin Trans. 1 1995, 303.
3
-Dimethylphenylsilyl-4,4-dimethylcyclohexanone (4)
Rf = 0.67 (cyclohexane–tert-butyl methyl ether, 2:1).
–
1
(12) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron Lett.
IR (film): 1713 (s) (C=O) cm .
1
988, 29, 4147. (b) Ogoshi, S.; Tomiyasu, S.; Morita, M.;
1
H NMR (500 MHz, CDCl ): d = 0.34 (s, 3 H), 0.37 (s, 3 H), 0.96
s, 3 H), 1.08 (s, 3 H), 1.37 (dd, J = 3.8, 14.0 Hz, 1 H), 1.65 (ddd,
J = 4.4, 6.6, 13.4 Hz, 1 H), 1.69 (ddd, J = 4.6, 13.5, 13.5 Hz, 1 H),
.22 (ddd, J = 2.0, 3.8, 15.3 Hz, 1 H), 2.26 (dddd, J = 2.0, 4.5, 4.5,
4.9 Hz, 1 H), 2.35 (ddd, J = 1.0, 14.0, 14.9 Hz, 1 H), 2.45 (ddd,
3
Kurosawa, H. J. Am. Chem. Soc. 2002, 124, 11598.
(
(
(
13) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc.
1
988, 110, 5579. (b) Matsumoto, Y.; Hayashi, T.; Ito, Y.
2
1
Tetrahedron 1994, 50, 335.
14) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, 2002, 224.
J = 0.8, 5.7, 14.2 Hz, 1 H), 7.30–7.36 (m, 3 H), 7.44–7.50 (m, 2 H).
1
3
C NMR (125 MHz, CDCl ): d = –2.2, –1.3, 23.7, 31.6, 33.3, 37.1,
8.2, 39.3, 44.2, 128.0, 129.2, 133.9, 138.6, 213.1.
3
(
(
15) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.;
Nasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
16) Gilman, H.; Lichtenwalter, G. D. J. Am. Chem. Soc. 1958,
80, 608.
3
+
LRMS (CI, NH ): m/z = 278 [M + NH ] .
3
4
Anal. Calcd for C H OSi (260.45): C, 73.79; H, 9.29. Found: C,
16
24
7
3.61; H, 9.18.
(17) Auer, G.; Oestreich, M. Chem. Commun. 2006, 311.
(
18) Fürstner, A.; Weidmann, H. J. Organomet. Chem. 1988,
54, 15.
3
Acknowledgment
(19) Analytical HPLC analysis on a chiral stationary phase using
a Daicel Chiralpak AD column (n-heptane–i-PrOH, 99:1 at
M.O. is indebted to the Deutsche Forschungsgemeinschaft for an
Emmy Noether fellowship (2001–2006) and to the Aventis Found-
ation for a Karl Winnacker fellowship (2006–2008). M.O. thanks
Professor Reinhard Brückner for continuous encouragement.
25 °C) provided baseline separation of enantiomers of 2:
9.69 min (minor enantiomer) and 10.8 min (major
enantiomer).
(
(
20) The low yield of 20% is in part due to the small scale, on
which extremely air- and moisture-sensitive KC was
8
handled.
References
21) (a) Weiner, B. Diploma Thesis; Albert-Ludwigs-Universität
Freiburg: Freiburg, Germany, 2004. (b) Auer, G. PhD
Dissertation; Albert-Ludwigs-Universität Freiburg:
Freiburg, Germany, 2006.
22) Okuda, Y.; Wakamatsu, K.; Tückmantel, W.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1985, 26, 4629.
23) Oestreich, M.; Auer, G. Adv. Synth. Catal. 2005, 347, 637.
(
1) Brook, M. A. Silicon in Organic, Organometallic and
Polymer Chemistry; Wiley: New York, 2000.
(
2) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(3) Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc. 1990, 112,
(
7793.
(
4) (a) Lipshutz, B. H. In Organometallics in Synthesis: A
Manual; Schlosser, M., Ed.; Wiley-VCH: Weinheim, 2002,
(
6
65. (b) Dieter, R. K. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002, 79.
c) Fleming, I. In Organocopper Reagents: A Practical
(
Approach; Taylor, R. J. K., Ed.; Oxford Academic Press:
New York, 1994, 257. (d) Tamao, K.; Kawachi, A. Adv.
Organomet. Chem. 1995, 38, 1.
Synthesis 2006, No. 13, 2113–2116 © Thieme Stuttgart · New York