Copper-catalyzed conjugate addition of a bis(triorganosilyl) zinc and a methyl(triorganosilyl) magnesium

Article abstract of DOI:10.1055/s-2004-831331

A practical copper-catalyzed conjugate silylation of α,β- unsaturated carbonyl compounds 4 utilizing bis(triorganosilyl) zinc reagent 3 is described. Moreover, mixed methyl(triorganosilyl) magnesium 7 also transfers its silyl ligand to simple enones 4 und

Full text of DOI:10.1055/s-2004-831331

LETTER
2139
Copper-Catalyzed Conjugate Addition of a Bis(triorganosilyl) Zinc and a
Methyl(triorganosilyl) Magnesium
C
opper-CatalyzedCon
a
jugate
A
dd
r
ition tin Oestreich,* Barbara Weiner
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 10 July 2004
1,4-additon of bis(triorganosilyl) zincs applicable to a
Abstract: A practical copper-catalyzed conjugate silylation of a,b-
wide variety of enones. Furthermore, if complete transfer
of the silyl ligand is desired, mixed alkyl(triorganosilyl)
magnesiums are also potent silyl group sources under cop-
per catalysis.
unsaturated carbonyl compounds 4 utilizing bis(triorganosilyl) zinc
reagent 3 is described. Moreover, mixed methyl(triorganosilyl)
magnesium 7 also transfers its silyl ligand to simple enones 4 under
copper catalysis.
Key words: catalysis, cuprates, silicon, zinc, copper
4 Li
2 PhMe2SiCl
2 PhMe2SiLi
THF
0 °C → −8 °C
−2 LiCl
1
2
The fundamental discovery of the stereoretentive oxida-
tion of a C–Si into a C–O bond (Tamao–Fleming oxida-
tion)1 has significantly amplified synthetic interest in C–
Si bond forming reactions and suitable reagents.2 Notably,
silyl cuprates have emerged as exceptionally effective re-
agents for such transformations.3 Introduction of a silicon
group via conjugate addition is usually effected using the
dark red
ZnCl2
(1.0 M
in Et2O)
O
1)
THF
0 °C
−2 LiCl
CuX
(5.0 mol%)
R1
O
R2
R3
Table 1
Methods A or B
4
R1
4
(PhMe2Si)2Zn
(PhMe2Si)2Cu(CN)Li2 reagent which is conveniently
2) NH4Cl
R2
R3
3
prepared from the corresponding silyl lithium and half-
stoichiometric amounts of CuCN.5 PhMe2SiLi (2) is em-
ployed in these reactions because of the ease of its
accessibility6 as well as the well-investigated oxidative
degradation1 of the PhMe2Si group.
SiMe2Ph
yellowish
brown
5
Scheme 1 Preparation and conjugate addition of (PhMe2Si)2Zn (3)
However, these synthetically valuable reagents2,3 are af-
flicted with two shortcomings as its use requires stoichio-
metric amounts of copper with only one of the two silyl
groups being transferred. In particular, equimolar quanti-
ties of copper salts are detrimental to large-scale reac-
tions. Accordingly, a user-friendly silyl cupration
catalytic in copper using stoichiometric amounts of the si-
lyl group is a worthwhile goal.
Bis(triorganosilyl) zincs have remained almost unnoticed
in organosilicon chemistry and synthetic applications
thereof are scarce.10,11 This is particularly surprising since
preparation and handling is simple as exemplified by the
synthesis of 3 (Scheme 1). Reductive metalation of silyl
chloride 1 (1 → 2) and subsequent admixture of 0.5
equivalents ZnCl2 (2 → 3) provides the requisite
(PhMe2Si)2Zn reagent 311 in almost quantitative yield.12a
These issues have been addressed by Nozaki,7 Lipshutz,8
and Hosomi9 and have led to three conceptually different
approaches: (i) 1,4-addition of the mixed zincate
PhMe2SiZnMe2Li in the absence of any copper catalyst,7
(ii) Me2Cu(CN)Li2-catalyzed (3.0 mol%) silyl cupration
employing mixed zincate PhMe2SiZnMe2Li,8 and (iii)
copper-catalyzed (5.0 mol%) conjugate silylation utiliz-
ing disilane (PhMe2Si)2.9 In the former processes the silyl
ligand is entirely delivered to the a,b-unsaturated acceptor
but needs handling of pyrophoric Me2Zn.7a,b,8
We have discovered that bis(triorganosilyl) zincs10 under-
go smooth conjugate addition in the presence of catalytic
amounts (5.0 mol%) of miscellaneous copper salts. Here-
in, we wish to report a practical reaction protocol for the
Additionally, silyl zincs are generally less basic and nu-
cleophilic than the corresponding silyl lithiums13a as veri-
fied in control experiments. Reagent 3 displayed less
reactivity towards ketones and esters which qualifies 3 as
a silyl transfer reagent in transition metal-catalyzed pro-
cesses such as conjugate addition reactions.14
We were pleased to find this assumption confirmed when
3 cleanly reacted with equimolar amounts of an enone 4 in
the presence of various copper salts15 (4 → 5,
Scheme 1).13b After an initial screening of reaction condi-
tions, we elaborated two protocols which differ in reaction
temperature (Method A: 2 h at –78 °C12b or Method B: >6
h at –20 °C12c). Independent of the copper source, these
worked equally well for 2-cyclohexenone (4a, Table 1,
entries 1–4).
SYNLETT 2004, No. 12, pp 2139–2142
0
1
.1
0
.2
0
0
4
Excellent yield was also obtained for the sterically more
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831331; Art ID: G26504ST
© Georg Thieme Verlag Stuttgart · New York
hindered g,g-dialkylated substrate 4b (Table 1, entry 5);

2140
M. Oestreich, B. Weiner
LETTER
furthermore, b,b-disubstituted isophorone (4c) underwent Conversely, aldehyde 4g was not compatible with Method
conjugate addition in good yield (Table 1, entry 6). These B showing considerable decomposition (Table 1, entry
enones required higher reaction temperatures (Method B) 17). Acceptable yield was seen at lower temperature
and CuI appeared to be superior to CuCN. However, ef- applying the mild Method A (Table 1, entry 16).
forts to accelerate this process by using additives such as
The above-described simple transmetalation step from
lithium to zinc (2 → 3, Scheme 1) overcomes the demand
for stoichiometric amounts of copper. This represents an
Me3SiCl16 (stoichiometric) or Sc(OTf)3 (catalytic)8 did
not result in any improvement of reaction rates.
Similarly, chalcone (4d) performed poorly applying alternative to the elegant methodologies introduced by
Method A (Table 1, entry 7) but yields greatly increased Lipshutz8 and Hosomi.9 Nevertheless, hypothetical inter-
at elevated temperature (Table 1, entries 8–10); CuI and mediate A generated by ligand exchange of (R3Si)2Zn and
Cu(OTf)2 were more effective than CuCN. Esters 4e and CuX only releases one silyl group to the a,b-unsaturated
4f provided the b-silylated products 5e and 5f in good iso- substrate B as illustrated in a simplified catalytic cycle
lated yields (Table 1, entries 11–15).
(Scheme 2). The other, non-transferable silyl ligand re-
Table 1 Conjugate Additon of 3 to a,b-Unsaturated Carbonyl Compounds 4a
Entry
Enone
Product
Catalyst
Method
Yield (%)b
1
2
3
4
CuCN
CuCN
CuI
A
B
B
B
90
80
85
85
O
O
Me
Me
Cu(OTf)2
Si
4a
Ph
5a
5
6
CuI
CuI
B
B
90
70
O
O
Me
Me
Si
Ph
4b
4c
5b
O
O
Me
Me
Si
Ph
5c
7
8
9
CuCN
CuCN
CuI
A
B
B
B
30
70
90
90
O
O
O
Me
Me
Ph
Si
O
Ph
Ph
10
Cu(OTf)2
Ph
Ph
4d
5d
Me
Me
11
12
13
14
CuCN
CuCN
CuI
A
B
B
B
70
80
80
80
Ph
Ph
Ph
Si
O
O
O
Me
OMe
OEt
Cu(OTf)2
Me
5e
Me
Me
OMe
OEt
H
4e
15
CuI
B
80
Si
Ph
4f
Ph
5f
Me
Me
16
17
CuCN
CuI
A
B
55
20
O
Si
Me
H
4g
Me
5g
a For Methods A and B see ref.12.
b Averaged yield (3 runs) of isolated analytically pure material.
Synlett 2004, No. 12, 2139–2142 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Conjugate Addition
2141
O
In summary, we have established the first synthetic appli-
cation of a bis(triorganosilyl) zinc reagent which is pre-
pared from a triorganosilyl lithium by straightforward
transmetalation using an etheral solution of ZnCl2. The
synthetic potential of this organometallic had been under-
estimated in the past, as we were able to demonstrate its
practical value as a silicon source in the copper-catalyzed
conjugate silylation of enones. Our facile reaction proto-
col is a useful alternative to known stoichiometric
variants3–5 and complements existing procedures which
are catalytic in copper.8,9 It is noteworthy that, in princi-
ple, this catalytic process is applicable to mixed
methyl(triorganosilyl) magnesiums which reduces squan-
dering of equimolar amounts of a silyl ligand. The devel-
opment of a catalytic asymmetric version of this reaction
is currently under investigation in our laboratories.
"R3SiCu"
A
R1
(+ R3SiZnX)
R2
R3
B
OZnSiR3
R1
(R3Si)2Zn
CuX
R2
R3
SiR3
C
Scheme 2 Simplified catalytic cycle17
mains in the zinc enolate C, which could possibly give
stoichiometric amounts of silicon-containing by-products.
Acknowledgment
These encouraging results prompted us to investigate the
copper-catalyzed conjugate addition of mixed alkyl(tri-
organosilyl) zincs and magnesiums (Scheme 3).18 This is
tempting since it is known from stoichiometric reactions
that the silyl ligand in mixed alkyl silyl cuprates is selec-
tively transferred from these reagents.18
The research was supported by the Deutsche Forschungsgemein-
schaft (Emmy Noether-Stipendium, Oe 249/2-3), the Fonds der
Chemischen Industrie, and the Wissenschaftliche Gesellschaft in
Freiburg im Breisgau. M. O. thanks Professor Dr. Reinhard
Brückner for his continuous support.
However, mixed methyl(triorganosilyl) zinc 6 performed
sluggishly and only minor amounts of product 5a were
formed along with decomposed starting material (4a →
5a, Scheme 3).
References
(1) For comprehensive reviews on the Tamao–Fleming
oxidation see: (a) Jones, G. R.; Landais, Y. Tetrahedron
1996, 52, 7599. (b) Fleming, I. Chemtracts, Org. Chem.
1996, 9, 1.
(2) (a) Brook, M. A. Silicon in Organic, Organometallic, and
Polymer Chemistry; Wiley-Interscience: New York, 2000.
(b) Colvin, E. W. Silicon Reagents in Organic Synthesis;
Academic Press: Orlando, 1988.
(3) (a) Lipshutz, B. H. In Organometallics in Synthesis. A
Manual; Schlosser, M., Ed.; Wiley-VCH: Weinheim, 2002,
665. (b) Dieter, R. K. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002, 79.
(c) Singer, R. D. In Science of Synthesis, Vol. 4; Ley, S. V.;
Fleming, I., Eds.; Thieme: Stuttgart, 2002, 231.
(d) Fleming, I. In Organocopper Reagents. A Practical
Approach; Taylor, R. J. K., Ed.; Oxford Academic Press:
New York, 1994, 257. (e) Tamao, K.; Kawachi, A. Adv.
Organomet. Chem. 1995, 38, 1.
To our surprise, the corresponding mixed methyl(triorga-
nosilyl) magnesium 711 reacted with 4a (1.01 equiv) at
–78 °C in the presence of CuCN (5.0 mol%) giving 5a in
moderate yield which improved slightly at higher tem-
perature (0 °C, Scheme 3). This transformation satisfies
the two essential requirements of an efficient silyl cupra-
tion since it is catalytic in copper and uses only one equiv-
alent of a silyl group. Though, yields are generally not as
high as for zinc reagent 3.
O
4a, CuCN
(5.0 mol%)
THF, 2 h
"Me(PhMe2Si)Zn⋅LiCl"
Me
Me
2) NH4Cl
6
Si
(4) (a) Lipshutz, B. H.; James, B. J. Org. Chem. 1994, 59, 7585.
(b) For Li[(PhMe2Si)2Cu]·LiCN see: Bertz, S. H.; Miao, G.;
Eriksson, M. Chem. Commun. 1996, 815.
<20%
at −78 °C and 0 °C
Ph
MeZnCl
(in Et2O)
THF
0 °C
5a
(5) (a) Ager, D. J.; Fleming, I. J. Chem. Soc., Chem. Commun.
1978, 177. (b) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem.
Soc., Perkin Trans. 1 1981, 2520. (c) Fleming, I.; Newton,
T. W.; Roessler, F. J. Chem. Soc., Perkin Trans. 1 1981,
2527. (d) For Et2NPh2SiCu(CN)Li see: Tamao, K.;
Kawachi, A.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 3989.
(e) For Li[PhMe2SiCuI] as its dimethylsulfide complex see:
Dambacher, J.; Bergdahl, M. Chem. Commun. 2003, 144.
(6) Gilman, H.; Lichtenwalter, G. D. J. Am. Chem. Soc. 1958,
80, 608.
PhMe2SiLi
2
MeMgl
(in Et2O)
THF
0 °C
O
4a, CuCN
(5.0 mol%)
THF, 2 h
"Me(PhMe2Si)Mg⋅LiI"
Me
Me
2) NH4Cl
7
Si
(7) (a) Tückmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber.
1986, 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,
5683.
65% at 0 °C
60% at −78 °C
Ph
5a
Scheme 3 Conjugate addition of mixed methyl(triorganosilyl) zinc
6 and magnesium 7
Synlett 2004, No. 12, 2139–2142 © Thieme Stuttgart · New York

2142
M. Oestreich, B. Weiner
LETTER
(8) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem.
Soc. 1998, 120, 4021.
extracted with MTBE (3 × 25 mL). The combined organic
phases were extracted with H2O (25 mL) and brine (25 mL).
After drying (Na2SO4), the solvents were evaporated under
reduced pressure and the resulting crude product 5 was
purified by flash chromatography on silica gel using
cyclohexane–MTBE solvent mixtures. (c) Method B: A
mixture of enone 4 (2.02 mmol, 1.01 equiv), CuX (5.0
mol%), and toluene (5 mL) was cooled to –20 °C. To this
mixture was then added 3 (2.00 mmol, 1.00 equiv) via
syringe. The reaction mixture was maintained at –20 °C for
>6 h and poured into sat. aq NH4Cl (25 mL). Work-up and
purification of 5 as described for Method A.
(9) (a) Ito, H.; Ishizuka, T.; Tateiwa, J.-i.; Sonoda, M.; Hosomi,
A. J. Am. Chem. Soc. 1998, 120, 11196. (b) See also: Clark,
C. T.; Lake, J. F.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 85. (c) For other catalyst systems see: Hayashi, T.;
Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 5579.
(d) Ogoshi, S.; Tomiyasu, S.; Morita, M.; Kurosawa, H. J.
Am. Chem. Soc. 2002, 124, 11598.
(10) Hameon, I.; Singer, R. D. In Science of Synthesis, Vol. 4;
Ley, S. V.; Fleming, I., Eds.; Thieme: Stuttgart, 2002, 225.
(11) For a single report on the preparation of 3 and an appli-
cation in a silyl metalation reaction see: Morizawa, Y.; Oda,
H.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1984, 25,
1163; this seminal publication also includes the magnesium
reagent 7.
(13) (a) This also applies to triorganosilyl zinc chlorides
(R3SiZnCl) prepared from R3SiLi and equimolar amounts of
ZnCl2. (b) Only traces of conjugate addition products 5 were
seen with R3SiZnCl under copper catalysis.
(12) (a) Preparation of Zinc Reagent 3: Phenyldimethylsilyl
chloride (1, 0.828 mL, 854 mg, 5.00 mmol, 2.50 equiv) was
maintained with freshly cut lithium (large excess) in THF
(10 mL) at –8 °C under argon atmosphere for 18 h. In order
to separate 2 (4.00 mmol, ca. 80% conversion; for a titration
procedure see ref.3d) from unreacted lithium metal, the
resulting dark red solution was transferred to another flask
via a double-ended cannula. At 0 °C, ZnCl2 (2.00 mL, 2.00
mmol, 1.00 equiv, 1 M in Et2O) was added accompanied by
a color change from red to yellowish brown. The reaction
mixture was maintained at this temperature for further 15
min and was ready to use. (b) Method A: A suspension of
CuX (5.0 mol%) and THF (5 mL) was pre-cooled to –78 °C
and treated with 3 (2.00 mmol, 1.00 equiv) via syringe. The
auburn reaction mixture was allowed to warm to 0 °C and
maintained at this temperature for 20 min. Addition of enone
4 (2.02 mmol, 1.01 equiv) to the re-cooled (–78 °C) reaction
mixture was followed by stirring for 2 h at –78 °C. Upon
completion of the reaction, the reaction mixture was poured
into sat. aq NH4Cl (25 mL) and the flask was rinsed with
MTBE (25 mL). The aqueous phase was separated and
(14) (a) It should be noted that Me3SiLi undergoes rapid 1,4-
additon to b-monosubstituted ketones in the absence of any
copper catalyst. See: Still, W. C. J. Org. Chem. 1976, 41,
3063. (b) Conversely, we have isolated substantial amounts
of the 1,2-adduct when treating enone 4a with PhMe2SiLi
(2).
(15) Cu(OTf)2 is believed to be reduced in situ as described for
the conjugate addition of dialkylzincs: Feringa, B. L.; Naasz,
R.; Imbos, R.; Arnold, L. A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002,
224.
(16) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26,
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Tetrahedron Lett. 1989, 30, 7087. (d) Alexakis, A.; Sedrani,
R.; Mangeney, P. Tetrahedron Lett. 1990, 31, 345.
(17) The generation of 3 from 1 produces a fourfold excess of
LiCl, which might function as a Lewis acid.
(18) (a) Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1991, 56,
770. (b) Singer, R. D.; Oehlschlager, A. C. J. Org. Chem.
1991, 56, 3510.
Synlett 2004, No. 12, 2139–2142 © Thieme Stuttgart · New York