Straightforward synthesis of α,β-epoxysilanes from terminal epoxides by lithium 2,2,6,6-tetramethylpiperidide-mediated deprotonation-in situ silylation

Article abstract of DOI:10.1016/S0040-4039(02)01893-2

Lithiation-in situ silylation of simple terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide in combination with trimethylsilyl chloride provides a direct and experimentally convenient process for the synthesis of trans-α,β-epoxysilanes.

Full text of DOI:10.1016/S0040-4039(02)01893-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7895–7897
Straightforward synthesis of a,b-epoxysilanes from terminal
epoxides by lithium 2,2,6,6-tetramethylpiperidide-mediated
deprotonation-in situ silylation
David M. Hodgson,a,* Nigel J. Reynoldsa and Steven J. Cooteb
aDyson Perrins Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 16 August 2002; accepted 5 September 2002
Abstract—Lithiation-in situ silylation of simple terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide in combination with
trimethylsilyl chloride provides a direct and experimentally convenient process for the synthesis of trans-a,b-epoxysilanes. © 2002
Elsevier Science Ltd. All rights reserved.
a,b-Epoxysilanes are synthetically valuable substrates
since, for example, they can be hydrolysed to produce
carbonyl compounds, undergo regioselective and
stereospecific ring-opening with a range of nucleophiles
to afford b-hydroxysilanes and serve as vinyl cation
equivalents for the preparation of olefins.1 Recently, we
reported the first direct deprotonation-electrophile trap-
ping of simple terminal epoxides with a silylating agent
present in situ to afford a,b-epoxysilanes, e.g. 3 from 1,
via a transient oxiranyllithium 2 (Scheme 1).2 The key
to achieving this transformation was the presence of a
suitable diamine ligand [(−)-sparteine, or ligands struc-
turally related to sparteine] at low temperature (−90°C).
aldehyde formation proceeds by rearrangement of an
oxiranyllithium (e.g. 2). Also, the low nucleophilicity of
LTMP is known to give it compatibility with certain
electrophiles, e.g. Me3SiCl,4 thus providing a way to
trap reactive lithiated intermediates in situ. We there-
fore considered that the use of LTMP as base could
provide an alternative and more experimentally conve-
nient approach to the in situ deprotonation-electrophile
trapping of terminal epoxides. Advantages of using
LTMP over an organolithium·(−)-sparteine (or
sparteine-like ligand) protocol, include ease of prepara-
tion from inexpensive, commercially available reagents
and greater functional group compatibility due to
lithium amide nature. Also, in contrast to (−)-sparteine,
the achiral nature of LTMP avoids issues concerning
partial kinetic resolution of racemic epoxides2 and the
different reactivity of separate epoxide enantiomers
(e.g. attempted silylation of (R)-1 with sBuLi·(−)-
sparteine failed, whereas (S)-1 gave 3 in 72% yield).5
In connection with our studies of the above transforma-
tion, we became interested in a report by Yamamoto
and co-workers on the selective isomerisation of termi-
nal epoxides to aldehydes using lithium 2,2,6,6-tetra-
methylpiperidide (LTMP).3 Yamamoto suggested that
A study of the LTMP-mediated in situ silylation of
1,2-epoxydodecane 1, with Me3SiCl as electrophile to
give trans-a,b-epoxysilane 3, has been made with an
investigation of the effect of varying the experimental
parameters (Scheme 2).
By addition of a solution of epoxide 1 and Me3SiCl to
LTMP (1:1.2:2.5 equiv., respectively) in THF it was
found that some silylation could be achieved at reaction
temperatures between −80°C and 20°C. Only a trace
amount of silylation was achieved at −80°C, while at
−45°C 3 was obtained in 20% isolated yield. Surpris-
ingly, given the supposed thermal instability of such an
Scheme 1.
Keywords: epoxides; lithiation; silicon and compounds.
* Corresponding author. Tel.: +44 (0)1865 275697; fax: +44 (0)1865
275674; e-mail: david.hodgson@chem.ox.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01893-2

7896
D. M. Hodgson et al. / Tetrahedron Letters 43 (2002) 7895–7897
Table 1. Direct synthesis of a,b-epoxysilanes from epox-
ides
Scheme 2.
unstabilised oxiranyl anion intermediate 2,2,6 reaction
at 20°C for 3 h gave 3 in 45% yield.7 Starting the
reaction at −78°C and allowing it to warm slowly to
20°C (over 16 h) with 2.5:1.5 equiv. LTMP/Me3SiCl in
THF afforded only a poor yield of 3 (16%). However,
an improvement was ultimately achieved by altering the
order of reagent addition, so that epoxide 1 was added
to LTMP pre-mixed with Me3SiCl. Although 3 was
obtained in low yield (24%) with 2.5 equiv. each of
LTMP and Me3SiCl in Et2O at 20°C for 6 h, this was
improved using 2.5:2 equiv. in THF at 0°C for 16 h
(50%). The best results were achieved using equimolar
quantities of LTMP and Me3SiCl, namely 3:3 and 5:5
equiv. at 0°C for 16 h in THF, producing 60% and 61%
isolated yields of 3, respectively. Further experimenta-
tion showed that excess Me3SiCl relative to LTMP
diminished the production of silylated epoxide 3, prob-
ably due to silylation of the lithium amide base, while
with LTMP in relative excess more epoxide was con-
sumed, but at the expense of increased levels of impuri-
ties. Also, addition of additives (TMEDA or DMPU)
did not lead to improved levels of silylation,8 but it was
found that silylation was also possible with the more
bulky Et3SiCl. With this electrophile the rate of oxi-
ranyl anion trapping was reduced, so excess Et3SiCl
was required to prevent otherwise predominant alde-
hyde formation (optimised result: 1.3:5 equiv. LTMP/
Et3SiCl provided 64% and 28% isolated yields of
silylated epoxide and dodecanal, respectively).3
The protocol involving epoxide addition to LTMP/
Me3SiCl (3:3 equiv.) in THF at 0°C was subsequently
applied to a number of more functionalised epoxides
49,10 to produce trans-a,b-epoxysilanes 5 (Scheme 3,
Table 1, entries 2–9).
(e.g. an internal reaction temperature of 0°C compared
to the strict −90°C required with the earlier diamine
ligand procedure).2 Interestingly, 5-(N-Boc-N-methyl-
amino)-1,2-epoxypentane gave the highest yield of silyl-
ated product (75%, entry 6) possibly due to rate
enhancement provided by coordination of LTMP to the
Boc functionality. Enantiopure (S)-1,2-epoxydodecane
gave a similar yield to that for the racemic epoxide
(entry 7). Glycidyl ethers were also successfully sub-
jected to the reaction conditions (entries 8 and 9).
Application of the silylation conditions to the 2,2-di-
substituted epoxide (entry 10) and the 1,2-disubstituted
epoxides (entries 11 and 12) afforded none of the
desired trisubstituted epoxides, with the starting epox-
ides being recovered in >80% yield. Presumably, LTMP
is too bulky to effect the deprotonation of these latter
epoxides,11 but this could allow the chemoselective silyl-
ation of a monosubstituted epoxide in the presence of a
disubstituted epoxide.
Moderate to good yields of a,b-epoxysilanes 5 were
obtained (56–75%, Table 1, entries 1–9), similar to
those previously reported using the organo-
lithium·diamine ligand procedure.2 It was later found
that reaction times shorter than 16 h at 0°C also gave
similar levels of silylation, even at an increased reaction
scale [e.g. using epoxide 1 (2.72 mmol) afforded, after 2
h at 0°C, 3 in 56% yield]. The present method using
LTMP as base is advantageous because it involves
much more experimentally straightforward conditions
Scheme 3.

D. M. Hodgson et al. / Tetrahedron Letters 43 (2002) 7895–7897
5. Norsikian, S. L. M., unpublished results.
7897
In conclusion, we have demonstrated that terminal
epoxides can be silylated under experimentally straight-
forward conditions with a simple lithium amide base
and silylating agent in situ. This chemistry provides an
alternative, concise and stereocontrolled conversion of
terminal epoxides to a,b-epoxysilanes without the need
for strictly controlled low temperature reaction condi-
tions, or the use of diamine ligands only available from
multistep synthesis. It has special merit for the synthesis
of enantiopure a,b-epoxysilanes,12 since enantiopure
terminal epoxides are now easily available by Jacobsen
hydrolytic kinetic resolution.13
6. (a) Satoh, T. Chem. Rev. 1996, 96, 3303–3325; (b) Hodg-
son, D. M.; Gras, E. Synthesis 2002, 1625–1642.
7. For an example of lithium amide-generated in situ trap-
ping of a thermally unstable carbenoid at 0°C, see:
Taguchi, H.; Yamamoto, H.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1977, 50, 1588–1591.
8. Attempts to silylate with Me3SiOTf or Me3Si-imidazole,
as well as trapping experiments with other electrophiles
(PhCHO, Ph2CO, BuOTf, Ph3SnCl) were unsuccessful.
9. Epoxides in Table 1 were commercially available or pre-
pared according to: (a) Elings, J. A.; Downing, R. S.;
Sheldon, R. A. Eur. J. Org. Chem. 1999, 837–846 (entry
3); (b) Yang, L.; Weber, A. E.; Greenlee, W. J.; Patchett,
A. A. Tetrahedron Lett. 1993, 34, 7035–7038 (entry 4); (c)
Rothberg, I.; Schneider, L.; Kirsch, S.; OFee, R. J. Org.
Chem. 1982, 47, 2675–2676 (entry 5); (d) 5-(N-Boc-N-
methylamino)-1,2-epoxypentane (entry 6) was synthesised
General procedure for a,b-epoxysilane preparation:
To a solution of 2,2,6,6-tetramethylpiperidine (141 mL,
0.835 mmol) in dry THF (2 mL) at 0°C under an argon
n
atmosphere was added dropwise BuLi (1.6 M in hex-
anes, 0.51 mL, 0.82 mmol). The mixture was allowed to
warm to 20°C over 30 min and then re-cooled to 0°C.
To this LTMP solution, Me3SiCl (104 mL, 0.816 mmol)
was added followed immediately by the appropriate
epoxide (0.272 mmol) in THF (1 mL). After stirring for
16 h at 0°C, satd aq. NH4Cl (2 mL) and Et2O (5 mL)
were added. The phases were separated and the
aqueous layer was extracted with Et2O (2×5 mL). The
combined organic layers were washed with brine (5
mL), dried (MgSO4) and concentrated under reduced
pressure. Purification of the residue by column chro-
matography (SiO2, pentane/ether) gave the a,b-
epoxysilane.
from 5-bromopentene by
a four-step sequence: (i)
HN(Boc)2, NaH, THF/DMF (3:1), 70°C, 6 h (75% yield);
(ii) TFA, CH2Cl2, 20°C, 20 h (69%); (iii) NaH, MeI,
THF/DMF (7.5:1), 20°C, 20 h (76%); and (iv) mCPBA,
CH2Cl2, 20°C, 4 h (79%); (e) Savle, P. S.; Lamoreaux, M.
J.; Berry, J. F.; Gandour, R. D. Tetrahedron: Asymmetry
1998, 9, 1843–1846 (entry 7); (f) Michnick, T. J.; Mat-
teson, D. S. Synlett 1991, 631–632 (entry 10); (g) cis-dec-
5-ene oxide (entry 11) was prepared in two steps from
dec-5-yne: (i) H2, Lindlar cat., quinoline, petroleum ether
(bp 40–60°C), 20°C, 24 h (86% yield); (ii) AcOOH,
Na2CO3, CH2Cl2, 20°C, 18 h (89%).
10. Data for 5-(N-Boc-N-methylamino)-1,2-epoxypentane:
wmax(neat)/cm−1 3053w, 2976m, 2932m, 2871w, 1694s,
1483m, 1396m, 1366m, 1160m, 881w, 772w; lH (400
MHz; CDCl3) 3.25 (2H, t, J=6.3 Hz, NCH2), 2.93 (1H,
m, CH), 2.84 (3H, s, NMe), 2.76 (1H, t, J=4.8 Hz, CH2),
2.48 (1H, dd, J=2.7 and 4.8 Hz, CH2), 1.75–1.54 (4H, m,
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for a
CASE award (to N.J.R.) and the EPSRC National
Mass Spectrometry Service Centre (Swansea) for mass
spectra.
t
2×CH2), 1.46 (9H, s, Bu); lC (100 MHz; CDCl3) 155.7
(CꢀO), 79.2 (CMe3), 51.9 (CH), 48.0 (NCH2), 47.0 (CH2),
34.0 (NMe), 29.6 (CH2), 28.4 (CMe3), 24.5 (CH2); m/z
(CI) 233 (10%, M+NH+4), 216 (90, M+H+), 177 (100), 160
(50), 116 (35); HRMS: found 216.1599 (M+H+),
C11H21NO3 requires 216.1599.
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