(2-methoxyphenyl)dimethylsilyl lithium and cuprate reagents offer unique advantages in multistep synthesis

Article abstract of DOI:10.1021/ol0165746

Equation presented The new silyllithium reagent 1 and the corresponding cyanocuprate 3 are readily generated under optimal conditions and are useful for the formation of C-Si bonds. Tamao-Fleming oxidation of such C-Si bonds can be effected under very mild conditions.

Full text of DOI:10.1021/ol0165746

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3337-3339
(2-Methoxyphenyl)dimethylsilyl Lithium
and Cuprate Reagents Offer Unique
Advantages in Multistep Synthesis†
Thomas W. Lee and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 14, 2001
ABSTRACT
The new silyllithium reagent 1 and the corresponding cyanocuprate 3 are readily generated under optimal conditions and are useful for the
formation of C−Si bonds. Tamao−Fleming oxidation of such C−Si bonds can be effected under very mild conditions.
Trialkyl/arylsilyllithium reagents now play a valuable role
in the synthesis of complex organic molecules because they
provide a unique avenue for the attachment of silyl groups
to carbon for use as control elements1,2 or as equivalents of
the hydroxyl function (via Tamao-Fleming oxidation3). The
most commonly used silyllithium reagent is PhMe2SiLi,
which is readily generated by reaction of PhMe2SiCl with
lithium metal.2b,c Surprisingly, this method of formation often
fails even for closely related silyl groups. In fact, Fleming
has published a paper describing the “failure in several
attempts to prepare arylsilyl-lithium reagents.”4 The most
striking example in that paper involved the simple replace-
ment of phenyl by p-tolyl, in which case the reaction afforded
only the corresponding disilane with no further conversion
to silyllithium reagent. It is generally agreed that at least
one phenyl group on silicon is necessary for the formation
of silyllithium reagent. The only exceptions to this rule are
tri-o-tolylsilyllithium, mesityldimethylsilyllithium, and hydrido-
dimesitylsilyllithium.2c,5 In each of these cases, silyllithium
reagent was probably generated directly from chlorosilane
without the intervention of disilane as a result of steric
shielding about the silicon center. The inaccessibility of many
silyllithium compounds is perhaps the reason PhMe2SiLi is
by far the most widely used reagent even though the Tamao-
Fleming oxidation of the PhMe2SiC subunit may fail in the
presence of sensitive functional groups.3
We recently reported an enantioselective total synthesis
of the marine natural product eunicenone A in which a silyl
group attached to carbon played a key role both in controlling
the position- and stereoselectivity of a catalytic enantio-
selective Diels-Alder reaction (Scheme 1) and as a precursor
of another functionality.6 During this research we examined
several new alternatives to the PhMe2Si group since this
structural subunit was marginal with regard to stereocontrol
and caused problems in a Tamao-Fleming oxidation.6 These
studies led to the discovery of (2-methoxyphenyl)dimethyl-
silyllithium (1) as a superior alternative to PhMe2SiLi, with
regard to both the electron-donating properties of the silyl
† Dedicated to Professor Ian Fleming.
(1) (a) Brook, M. A. Silicon in Organic, Organometallic and Polymer
Chemistry; Wiley: New York, 2000. (b) Colvin, E. W. Silicon Reagents in
Organic Synthesis; Academic Press: London, 1988. (c) Webber, W. P.
Silicon Reagents in Organic Synthesis; Springer: Berlin, 1983. (d) Colvin,
E. W. Silicon in Organic Synthesis; Butterworths: London, 1981. (e)
Fleming, I.; Barbero, A.; Walker, D. Chem. ReV. 1997, 97, 2063.
(2) (a) Lickiss, P. D.; Smith, C. M. Coord. Chem. ReV. 1995, 95, 75. (b)
Fleming, I. In Organocopper Reagents: A Practical Approach; Taylor, R.
J. K., Ed.; Oxford University Press: Oxford, 1994; pp 257-292. (c) George,
M. V.; Peterson, D. J.; Gilman, H. J. Am. Chem. Soc. 1960, 82, 403.
(3) (a) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1. (b) Jones, G.
R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(5) (a) Mu¨ller, H.; Weinzierl, U.; Seidel, W. Z. Anorg. Allg. Chem. 1991,
603, 15. (b) Weidenbruch, M.; Kramer, K. Z. Naturforsch., B: Chem. Sci.
1985, 40B, 601.
(4) Rahman, N. A.; Fleming, I.; Zwicky, A. B. J. Chem. Res., Miniprint
1992, 2401.
(6) Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 1872.
10.1021/ol0165746 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/05/2001

-50 °C initially and then at 0 °C for 1.5 h affords a cuprate
(3) reagent of the type (ArMe2Si)2CuCNLi2, which undergoes
smooth coupling at -50 °C with (E)-geranyl benzoate to
form 4 (80%) and with (E,E)-sorbyl benzoate to form 5
(72%). Reaction of this cuprate with 2-cyclohexenone
provided the conjugate adduct 6 (80%) (Scheme 3).
Scheme 1
Scheme 3
group and Tamao-Fleming oxidation of sensitive substrates.
This paper reports on the generation of 1 and its use in
synthesis and also on some related new reagents which,
although not suited for the synthesis outlined in Scheme 1,
are probably useful for other applications.
The generation of 1 was carried out from the disilane 2,
which was synthesized by the reaction of 2-methoxyphen-
yllithium with commercially available sym-dichlorotetra-
methyldisilane (Scheme 2).7 The conditions for the formation
The (2-methoxyphenyl)dimethylsilyl group offers some
advantages over the parent phenyldimethylsilyl group be-
cause it can be converted oxidatively to an alcohol moiety
under much milder conditions and is effectively a more
potent σ f π electron donor.6 We found that the 2-meth-
oxyphenyl group in 7 undergoes facile Ar-Si cleavage by
the action of N-bromosuccinimide or trifluoroacetic acid, as
shown in Scheme 4. The resulting succinimido- or trifluo-
Scheme 2
Scheme 4
of 1 from 2 were found to be critical. Methyllithium was
superior to n-BuLi for the reaction, and the optimum
temperature was found experimentally to be -50 °C with
4:1 THF/hexamethylphosphoric triamide (HMPA)8 as sol-
vent. The appreciable instability of solutions of 1 at -30 °C
precludes the use of this or higher temperature for its
generation from 2. Solutions of 1, which are dark red in color,
produce (2-methoxyphenyl)dimethylsilane upon treatment
with methanol. Reaction of 1 with 0.5 equiv of CuCN at
roacetoxysilane can then be oxidized under very mild
conditions to provide 3-phenylpropanol in good yield.
We have also prepared a series of reagents analogous to
1 but differing in the aryl part using the same method of
generation, i.e., reaction of (ArMe2Si)2 with MeLi in 4:1
THF/HMPA at -50 °C. In this way we obtained the lithium
reagents 8-10 and by further reaction with CuCN also the
cuprates (ArMe2Si)2CuCNLi2. The cuprates from 8-10
underwent smooth coupling with (E)-geranyl and (E,E)-
sorbyl benzoate and conjugate addition with 2-cyclohexenone
to form the corresponding organosilicon products,9 the results
being very similar to those obtained with cuprate 3 (seven
examples, 81-96% yield, see Supporting Information for
details).
(7) The conditions described herein were arrived at after extensive
experimentation. Many methods previously used for preparing PhMe2SiLi
failed to afford the desired silyllithium reagent 1. Attempts to generate 1
from (2-methoxyphenyldimethyl)silyl chloride with lithium metal in THF
were unsuccessful (see also ref 4). Attempts to prepare 1 or its potassium
analogue from (2-methoxyphenyl)dimethylsilane by deprotonation with LDA
or KHMDS in THF or KH in DME were unpromising. The reaction of
ArMe2SiH with n-BuLi or t-BuLi led to displacement of H by n-Bu or Me
by t-Bu, respectively.
(8) (a) Still, W. C. J. Org. Chem. 1976, 41, 3063. (b) Hudrlik, P. F.;
Waugh, M. A.; Hudrlik, A. M. J. Organomet. Chem. 1984, 271, 69. (c)
The HMPA/THF ratio and reactant concentration were optimized to ensure
a reasonable reaction rate and a homogeneous mixture at -50 °C.
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Org. Lett., Vol. 3, No. 21, 2001

In addition, the chemistry reported above is applicable to
the preparation of other silyllithium reagents such as, but
not limited to, 8-10.
Acknowledgment. We are grateful to the National
Science Foundation and Boehringer Ingelheim Co. for
graduate fellowships to T.W.L.
In summary, the studies reported herein have led to the
discovery of the new organosilyllithium reagent 1, which
has considerable potential in multistep synthesis. Very mild
conditions for effecting the hydroxy desilylation reactions
of the (2-methoxyphenyl)dimethylsilyl group are described.
Supporting Information Available: Full procedures for
the generation of organosilyllithium reagents 1 and 8-10
and the corresponding cyanocuprates, along with examples
of their use, and oxidative desilylation of 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Various furylsilyl reagents have previously been applied in synthesis;
see: (a) Norley, M. C.; Kocienski, P. J.; Faller, A. Synlett 1994, 77. (b)
Hunt, J. A.; Roush, W. R. Tetrahedron Lett. 1995, 36, 501. (c) Stork, G.
Pure Appl. Chem. 1989, 61, 439.
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