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Diethyl lithiomaleate: Preparation and use in synthesis
TetrahedronLetters,Vol. 35. No. 48, pp. 9101-9102.1994 Elswia scimce Lxd Printedin Cmat Britain (mo-4039194$7.00+0.00
oo4o-4o39(94)01944-4
Diethyl Lithiomaleate: Preparation and Use in Synthesis. David C. Harrowven* Department
of Chemistry,
University
and Hon Suen Peon
of Wales, Bangor, Gwynedd,
LL57 2LJW.l
Abstract : The paper describes u simple method fur the generation and alkylation of diethyl These reactions proceed with complete rerentinn of alkene geometry. providing a
lithiomaleate.
convenient methodfor the diastereosciective introduction of this us@lfour
The ability of many heteroatoms centres
unlike their radical counterparts,
to facilitate
are configurationally
As part of some ongoing
cndeavours.3
the deprotonation
interest. 2 An attractive
has inspired much current
studies
the podophyllin
Clearly the most attractive
symhon for the diethyl maleate anion. to report our realisation
of that objective
for the diastereoselective
introduction
of neighbouring
aspect of this chemistry
unsaturated
lignans.
useful in
we had cause
and strategically
carbon
is that alkenyl anions,
stable making them particularly
towards
achieve this aim was to effect the direct deprotonation
carbon synthnn.
synthetic
to desire a
the simplest method to
of diethyl maleate (Scheme).4
In this letter we wish
and highlight the ease with which this method may be employed
of this highly ftmctionalised
four carbon fragment
Scheme Our favouted cooled
(-78oC)
method
so&ion
to accomplish
this transformation
of IV-lithio-2.2.6.~tetramethylpiperidine
quench the partially formed anion with a trap (2 mmol). good to moderate conditions
is to add diethyl maleate
yie.ki flable).
(5 mmol) to a
(5 mmol) in THF and then immediately
In this way the desired adducts may be formed in
7l’te use of LDA or LiHMDS
was found to be less satisfactory under ah
explored.
In each of the cases studied the teaction both simple and complex
substrates,
the alkene
was
observed.
exclusively,
for (R)-carvone
With
was found to be highly selective
e.g. the podophyllin a&unsaturated
providing
precursor
ketones
vable
the product
the adduct & a &ngk enantion&r
Despite of the use of excess of base, yields were not diminished
9101
and proceeded
entry F).s
well with
No isomcrisation
of l&addition
of
was formed
in 68% yield (Table entry D).
with enolisable
ketones.
Table: Coupling
Reactions of Diethyl Lithionraleate
Electroph ile
with Ketones. Adduct and Yield
Adduct and Yield
I
OH
PhS
Ph
kx
D
CO@
0
51%
0
E
0
82 CO@
0 C
6
CO$t 63%
The reaction was less satisfactory with aldehydes.
47%
For example, when 3,4.5-trimethoxybenzaldehyde
was used in this sequence the adduct was provided in c.a. 30% yield, together with copious quantities of 3.4.5~uimethoxybenzyl alcohol. We are presently investigating a number of extensions of this methodology and if’s application in target orientated synthesis. Acknowledgement:
The authors wish to thank the Nuffteld Foundation
and The University of Wales,
Bangor for their support of this programme. References and Notes:
1. 2.
Prcscnt address: Department Southampton, So9 5NH.
of
Chemistry,
The
University
of
Southampton,
Highfield,
For some excellent reviews of heteroatom facilitated lithiation reactions see: a. Snieckus, V. Chem. Rev., 1990, 90, 879; b. Gschwend, H.W.; Rodriguez, H.R. Org. React.,
Grganometallics
1979, 26, 1. c. Wii,
in Synthesis: Main Group Elements. In Gcrreral and Synthefic Metho&.
M.
Pattenden
G. Ed., RSC: Cambridge. 1994, Vol. 16, Ch. 6ii, pp. 320 and previous articles in this series. 3. 4.
Jenkins. P.R.; Symons. M.C.R.; Booth, S.E.; Swain, C.J. TetrahedronLett.. 1992,33,3543. Examples of metallation reactions solely assisted by esters are scant. See: a. Upton, C.J.; Beak, P. J. Org. Chern., 1975, 40, 1094; b. Beak, P.; McKinnie, B.G. J. Am. Chem. Sot., 1977, 99. 5213; c Olofson. R.A.; Lotts, K.D.; Barber, G.N. Tetrahedron Lett., 1976. 3381. d. Miyata, 0; Schmiit, R.R. Angew. Chem., Int. Ed. Et@., 1982, 21, 637 and e. Schmidt. R.R.; Talbiersky, J.; Russegger,
5.
P. J. Am. Chem. Sac.. 1977.99.5213 may also be of interest. a. Harrowven, D.C.; Tetrahedron, 1993. 49, 9039; b. Harrowven, Tetrahedron
Lett., 1993.34.3323;
(Received in UK 22 September
c. Harrowven. DC;
DC.;
Dennison,
Tetrahedron Lea., 1991.32,3735.
1994; accepted 30 September 1994)
S.T.
oo4o-4o39(94)01944-4
Diethyl Lithiomaleate: Preparation and Use in Synthesis. David C. Harrowven* Department
of Chemistry,
University
and Hon Suen Peon
of Wales, Bangor, Gwynedd,
LL57 2LJW.l
Abstract : The paper describes u simple method fur the generation and alkylation of diethyl These reactions proceed with complete rerentinn of alkene geometry. providing a
lithiomaleate.
convenient methodfor the diastereosciective introduction of this us@lfour
The ability of many heteroatoms centres
unlike their radical counterparts,
to facilitate
are configurationally
As part of some ongoing
cndeavours.3
the deprotonation
interest. 2 An attractive
has inspired much current
studies
the podophyllin
Clearly the most attractive
symhon for the diethyl maleate anion. to report our realisation
of that objective
for the diastereoselective
introduction
of neighbouring
aspect of this chemistry
unsaturated
lignans.
useful in
we had cause
and strategically
carbon
is that alkenyl anions,
stable making them particularly
towards
achieve this aim was to effect the direct deprotonation
carbon synthnn.
synthetic
to desire a
the simplest method to
of diethyl maleate (Scheme).4
In this letter we wish
and highlight the ease with which this method may be employed
of this highly ftmctionalised
four carbon fragment
Scheme Our favouted cooled
(-78oC)
method
so&ion
to accomplish
this transformation
of IV-lithio-2.2.6.~tetramethylpiperidine
quench the partially formed anion with a trap (2 mmol). good to moderate conditions
is to add diethyl maleate
yie.ki flable).
(5 mmol) to a
(5 mmol) in THF and then immediately
In this way the desired adducts may be formed in
7l’te use of LDA or LiHMDS
was found to be less satisfactory under ah
explored.
In each of the cases studied the teaction both simple and complex
substrates,
the alkene
was
observed.
exclusively,
for (R)-carvone
With
was found to be highly selective
e.g. the podophyllin a&unsaturated
providing
precursor
ketones
vable
the product
the adduct & a &ngk enantion&r
Despite of the use of excess of base, yields were not diminished
9101
and proceeded
entry F).s
well with
No isomcrisation
of l&addition
of
was formed
in 68% yield (Table entry D).
with enolisable
ketones.
Table: Coupling
Reactions of Diethyl Lithionraleate
Electroph ile
with Ketones. Adduct and Yield
Adduct and Yield
I
OH
PhS
Ph
kx
D
CO@
0
51%
0
E
0
82 CO@
0 C
6
CO$t 63%
The reaction was less satisfactory with aldehydes.
47%
For example, when 3,4.5-trimethoxybenzaldehyde
was used in this sequence the adduct was provided in c.a. 30% yield, together with copious quantities of 3.4.5~uimethoxybenzyl alcohol. We are presently investigating a number of extensions of this methodology and if’s application in target orientated synthesis. Acknowledgement:
The authors wish to thank the Nuffteld Foundation
and The University of Wales,
Bangor for their support of this programme. References and Notes:
1. 2.
Prcscnt address: Department Southampton, So9 5NH.
of
Chemistry,
The
University
of
Southampton,
Highfield,
For some excellent reviews of heteroatom facilitated lithiation reactions see: a. Snieckus, V. Chem. Rev., 1990, 90, 879; b. Gschwend, H.W.; Rodriguez, H.R. Org. React.,
Grganometallics
1979, 26, 1. c. Wii,
in Synthesis: Main Group Elements. In Gcrreral and Synthefic Metho&.
M.
Pattenden
G. Ed., RSC: Cambridge. 1994, Vol. 16, Ch. 6ii, pp. 320 and previous articles in this series. 3. 4.
Jenkins. P.R.; Symons. M.C.R.; Booth, S.E.; Swain, C.J. TetrahedronLett.. 1992,33,3543. Examples of metallation reactions solely assisted by esters are scant. See: a. Upton, C.J.; Beak, P. J. Org. Chern., 1975, 40, 1094; b. Beak, P.; McKinnie, B.G. J. Am. Chem. Sot., 1977, 99. 5213; c Olofson. R.A.; Lotts, K.D.; Barber, G.N. Tetrahedron Lett., 1976. 3381. d. Miyata, 0; Schmiit, R.R. Angew. Chem., Int. Ed. Et@., 1982, 21, 637 and e. Schmidt. R.R.; Talbiersky, J.; Russegger,
5.
P. J. Am. Chem. Sac.. 1977.99.5213 may also be of interest. a. Harrowven, D.C.; Tetrahedron, 1993. 49, 9039; b. Harrowven, Tetrahedron
Lett., 1993.34.3323;
(Received in UK 22 September
c. Harrowven. DC;
DC.;
Dennison,
Tetrahedron Lea., 1991.32,3735.
1994; accepted 30 September 1994)
S.T.