Reactions of phenyldimethylsilyllithium with β-N,N-dimethylaminoenones

Article abstract of DOI:10.1039/b210444j

Phenyldimethylsilyllithium reacts with the β-N,N-dimethylaminoenones 1 and 7, with the enal 5, and with ethyl β-N,N-dimethylaminoacrylate 9 to give the corresponding α,β-unsaturated carbonyl compounds with a β-phenyldimethylsilyl group, but in the last ca

Full text of DOI:10.1039/b210444j

Reactions of phenyldimethylsilyllithium with
b-N,N-dimethylaminoenones
Ian Fleming,* Elena Marangon, Chiara Roni, Matthew G. Russell and Sandra Taliansky Chamudis
Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW. E-mail: if10000@cam.ac.uk; Fax: 44
1223 336362; Tel: 44 1223 336372
Received (in Cambridge, UK) 29th October 2002, Accepted 9th December 2002
First published as an Advance Article on the web 17th December 2002
Phenyldimethylsilyllithium reacts with the b-N,N-dimethyl-
aminoenones 1 and 7, with the enal 5, and with ethyl b-N,N-
seems likely that the conjugate addition–elimination pathway is
followed in all of these reactions.
dimethylaminoacrylate
9
to give the corresponding
In any case, the products 2, 6 and 8 are easily made by other
methods,7–9 and so we have not taken this investigation any
further. Instead we investigated the corresponding reaction with
the vinylogous carbamate 9, which gave us a curious result, and
a better synthesis of the ester 12 than the one we had been using
hitherto in our synthetic work
When we added the silyllithium reagent to the ester 9 and
quenched with sodium bicarbonate solution, the only product
was that of conjugate addition, 11 (Scheme 2). While this is an
unsurprising result in itself, it raised the first question: why was
the dimethylamino group eliminated in the experiments in
Scheme 1, and not here? One possibility is that the ketone and
aldehyde enolates are kinetically protonated on oxygen. The
resultant enols might then live long enough to expel the
dimethylamino group in the protic medium before they
underwent tautomerism to the ketones or the aldehyde. In
contrast, it is possible that the ester enolate is protonated
directly on carbon, and the dimethylamino group would not then
be easily lost.10
However, this was not the most puzzling observation. If,
instead of the aqueous quench, we added methyl iodide, and
then worked up in the usual way, the major product was the b-
silylester 12. This was not the result that we expected, because
the enolate ion in the intermediate 10 ought to have been more
nucleophilic towards methyl iodide than the dimethylamino
group. The product of enolate methylation 13 was detectable
only in small amounts. Similarly, when we regenerated the
enolate 10 from the ester 11 using LDA, and treated that enolate
with methyl iodide, the same unsaturated ester 12 was
formed.
Additionally remarkable is that the elimination of dimethyl-
amine 10 ? 12 achieved by the treatment with methyl iodide
took only 10–20 min at 220 °C. In contrast, if we treated the
amine 11 with methyl iodide in THF at room temperature, little
N-methylation took place over 18 h—we recovered the amine
11 in 86% yield. Evidently, the a-silyl group does not on its own
increase the nucleophilicity of the nitrogen lone pair11 enough
to account for the ease of N-methylation, and we have no
convincing explanation for the ease with which the elimination
took place. It is not specific to using methyl iodide, since benzyl
chloride and allyl bromide had the same effect, although not in
such good yield. The most obvious explanation would have
a,b-unsaturated carbonyl compounds with a b-phenyl-
dimethylsilyl group, but in the last case only when the
reaction mixture is given a mysteriously brief treatment with
methyl iodide before workup.
In the preceding communication1and its predecessors,2–4 we
described several remarkable reactions of the phenyldimethyl-
silyllithium reagent with N,N-dimethylamides. In this commu-
nication we describe the somewhat less surprising reactions
with four of their vinylogous counterparts.
The reaction with the enone 1 was unexceptional in giving
overall substitution of the dimethylamino group by the silyl
group (Scheme 1). Two pathways might have been followed. In
one, the silyllithium reagent attacked the carbonyl group
directly to give the enamine 3, hydrolysis of which, followed by
elimination of water, would give the enone 2. Alternatively,
conjugate attack took place to give the enolate 4, which
underwent elimination of the dimethylamino group. A similar
outcome was found for the enal 5 giving the enal 6, in a less
clean reaction with the same two possible pathways. The
conjugate addition–elimination pathway is certainly followed in
the reaction between the silyllithium reagent and the enone 7,
which gave the b-silylenone 8 in good yield. Furthermore, it is
known that a b-amino group encourages conjugate addition by
organolithium reagents,5 and trimethylsilyllithium is also
known to give conjugate addition, rather than direct attack at the
carbonyl group, with cyclohexenones.6 Finally, it is not obvious
why the pathway involving direct attack at the carbonyl group
should not enter the carbene-forming sequence that we have
seen is so accessible in the reactions described earlier.1–4 It
Scheme 1 Reagents and conditions: i, PhMe2SiLi, 278 °C, 1 h, 220 °C 1
h; ii, NaHCO3, H2O.
Scheme 2 Reagents and conditions: i, PhMe2SiLi, THF, 278 °C, 2 h,220
°C 1 h; ii, NaHCO3, H2O; iii, MeI, 10–20 min; iv, LDA, THF, 278 °C.
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CHEM. COMMUN., 2003, 200–201
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been that the dimethylamide ion had already been expelled from
the enolate 10 before the aqueous quench, and had added back
during the aqueous quench. The role of the methyl iodide in this
scenario would have been to quench the dimethylamide ion, and
prevent it from adding back. This is not the explanation, because
the unsaturated ester 12, which would have been the product of
that elimination, reacted with lithium dimethylamide to give the
amides 14 and 15 (Scheme 3). These products were not present
in the reaction mixtures from Scheme 2. Furthermore, quench-
ing the reaction mixture from the conjugate addition by
injecting it directly into aqueous hydrochloric acid gave largely
the ester 11 (67%) and only a little (9%) of the product of
elimination 12.
this problem. For further development, it was helpful to
saponify the crude ester 12, in order to separate acidic products
from silicon-containing byproducts. The carboxylic acid occa-
sionally crystallised, but recrystallisation, either of the acid or of
its various salts was not practical. Since we needed it attached to
Oppolzer’s auxiliary, as did he,15 we converted the acid into its
acid chloride and joined it onto the auxiliary (Scheme 5), at
which point we had a crystalline derivative 21 that could be
purified by recrystallisation. The overall yield of this useful
compound from the amino ester 9 was 41%.
The easy elimination induced by methyl iodide has some-
thing to do with the presence of the silyl group. We repeated the
reaction with the ester 9 using phenyllithium instead of
phenyldimethylsilyllithium (Scheme 4). Conjugate addition
took place to give the enolate 16; quenching with ammonium
chloride solution gave the amino ester 17; but quenching with
methyl iodide gave the expected enolate methylation, with the
expected12 high degree of diastereoselectivity in favour of the
known13 isomer 18.
The ester 12 has usually been prepared most economically by
hydrosilylation–dehydrogenation of ethyl acrylate,14 but in that
otherwise excellent method it is always contaminated with the
saturated analogue, no matter how much of an excess of ethyl
acrylate is used to limit the amount of hydrosilylation. In our
experience, removing the saturated analogue has frequently
been difficult, while the new synthesis reported here is free of
Scheme 5 Reagents and conditions: i, KOH, MeOH, H2O, rt, 1.5 h; ii,
(COCl)2, DMF, CH2Cl2, rt, 1 h; iii, 20, THF, 278 °C, ? rt, 1 h.
This work was supported by research grant (RG/M17013)
from the EPSRC (for MGR), and by the ERASMUS scheme
(for S. T.), to both of which we are grateful. We also thank the
Department of Pharmaceutical Sciences, University of Padua
for arranging summer visits (for E. M. and C. R.).
Notes and references
1 I. Fleming and M. Russell, Chem. Commun., 2003, 198.
2 I. Fleming, U. Ghosh, S. R. Mack and B. P. Clark, Chem. Commun.,
1998, 711.
3 I. Fleming, S. R. Mack and B. P. Clark, Chem. Commun., 1998, 713.
4 I. Fleming, S. R. Mack and B. P. Clark, Chem. Commun., 1998, 715.
5 R. F. Abdulla and K. H. Fuhr, J. Org. Chem., 1978, 43, 4248; T.
Mukaiyama and T. Ohsumi, Chem. Lett., 1983, 875; C. Fontenas, H.
Aït-Haddou, E. Bejan and G. G. A. Balavoine, Synth. Commun., 1998,
28, 1743.
6 W. C. Still and A. Mitra, Tetrahedron Lett., 1978, 2659.
7 I. Fleming and D. A. Perry, Tetrahedron, 1981, 37, 4027.
8 I. Fleming and N. D. Kindon, J. Chem. Soc., Perkin Trans. 1, 1995,
303.
Scheme 3 Reagents and conditions: i, Me2NLi, THF, 278 °C, 0.5 h, 220
°C, 1 h; ii, NaHCO3, H2O.
9 I. Fleming, T. W. Newton, V. Sabin and F. Zammattio, Tetrahedron,
1992, 48, 7793.
10 We thank Professor Barry Trost for this suggestion.
11 This effect of an a-silyl group is known: K. J. Shea, R. Gobeille, J.
Braunblett and E. Thompson, J. Am. Chem. Soc., 1978, 100, 1611.
12 S. G. Davies and I. A. S. Walter, J. Chem. Soc., Perkin Trans. 1, 1994,
1129; S. G. Davies, O. Ichihara and I. A. S. Walter, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1141.
13 E. Graf and M. Graser, Arch. Pharm. (Weinheim, Ger.), 1969, 302,
665.
14 K. Takeshita, Y. Seki, K. Kawamoto, S. Murai and N. Sonoda, J. Org.
Chem., 1987, 52, 4864.
Scheme 4 Reagents and conditions: i, PhLi, Et2O, 210 °C, 0.5 h, rt, 1 h; ii,
NH4Cl, H2O; iii, (from 9) MeI, 15 h; iv, LDA, THF, 278 °C; v, (from 17)
MeI, 278 °C, 0.5 h, rt, 1 h.
15 W. Oppolzer, R. J. Mills, W. Pachinger and T. Stevenson, Helv. Chim.
Acta., 1986, 69, 1542; see also: C. Palomo, J. M. Aizpurua, M. Iturburu
and R. Urchegui, J. Org. Chem., 1994, 59, 240.
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