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Stereoselective conjugate additions of sulphoxide stabilised carbanions to α,β-unsaturated esters
Tetrahedron Printed in
Letters,Vol.29,No.45,pp Great Britain
STEREOSELECTIVE
5821-5824,1988
CONJUGATE
CARBANIONS
ADDITIONS
0040-4039/88 $3.00 Pergamon Press plc
OF SULPHOXIDE
TO a$-UNSATURATED
+ -00
STABILISED
ESTERS
M. Casey,* A.C. Manage, and, in part, L. Nezhat Department of Chemistry and Applied Chemistry, University of Salford, Salford M5 4WT
Summaqv: The reaction of Iithiated a&l t-butyl sulphoxides with a&unsaturated
esters gives conjugate
addition products in good yield, with high stereoselectivity. Asymmetric
conjugate additions to a&unsaturated
carbonyl compounds have been the subject of
much attention, in keeping with the importance of these reactions in stereoselective stereoselectivity
has been achieved by incorporating
synthesis.
Excellent
a chiial auxiliaty into the electrophilic component1 and
more recently there have been notable successes using chiral nucleophiles, especially enolates2 and organocopper
reagents3
In the course of a wider survey of the use of lithiated sulphoxides as chiral nucleophiles surprised to find that the conjugate addition of a-sulphinyl has received little attention.
carbanions to a&unsaturated
we were
carbonyl compounds
The anions of ally1 sulphoxides add to enones with high regio- and stereoselectivity
and this reaction has been studied in detail by several groupsp culminating in elegant synthetic applications.5 Other sulphoxides
bearing a second anion stabilising group, such as a-arylthiosulphoxides6
esters,7 undergo less selective conjugate additions. sulphoxides
However, to our knowledge,
and a-sulphinyl
the use of simple alkyl
has not been reported, apart from conjugate additions to vinyl sulphoxides,*
and a mention of
conjugate addition to enoates as a side reaction to acylation.9 We have found that the anions derived from alkyl t-butyl sulphoxides
1 can be added to a$-
unsaturated esters, to give conjugate addition products 2 with very little competing acylation, and now present a preliminary report on the scope and stereoselectivity
of this reaction.
(i) LDA, THF. -78”
(iii)
H,O’
2
I
Reactions were carried out by adding precooled solutions of a&unsaturated alkyl sulphoxides
in THF at low temperatures
esters to lithiated t-butyl
and the results for a model sulphoxide la are shown in Table 1.
Addition to methyl acrylate proceeded smoothly giving the conjugate addition product 2a with no trace of competing stereoisomer
1,2-addition. subsequently
Moreover the n.m.r. of the crude product showed it to consist largely (2 5: l)lu of one assigned (see below) as 2a. The addition to methyl crotonate was also quite clean.
Although a trace of acylation product was observed a good yield of the conjugate addition product 2b was
5821
5822
Table 1 Sulphoxide
a$-Unsaturated
V S
Prod&
Yieldb
0
6””
la Ph
Ester
2a, 64%
&fdOMe
\ -A
OMe
z
>
0 B”tj’& Al
OMe
2b,
68%
2c,
63%
4,
38%
:
OMe Phj
JJdOMe Phd
OMe Ph’
/
‘:
O
3 0
(7
S
a. The n.m.r. (lH and
v
13C),ix., and mass spectra of the products were fully consistent with the structures shown.
b. Yields refer to stereoisomerically
obtained.
/
But’ Ph
OH
O
pure products.
The most notable feature of this addition is that it proceeded with high stereoselectivity,
diastereomer
being formed almost exclusively (2 10: 1). lo The relative stereochemistry
one
of the product was
determined by X-ray crystal structure analysis 11 and a computer generated drawing of the molecule is shown in Figure 1. The stereochemistry
of the other conjugate addition products was assigned by analogy with this
example and by detailed analysis of the n.m.r. spectra of the adducts. l2 Reaction of the lithiated sulphoxide with methyl cinnamate provided the conjugate addition product 2c with high stereoselectivity. In contrast, reaction with an unsaturated lactone 3 gave none of the desired conjugate addition product, a mixture of stereoisomers
of the acylated sulphoxide 4 being formed instead. Another limitation is that
addition to tiglate esters gave mixtures of products containing some acylation products, unreacted starting material, and only small amounts of the conjugate addition products. sulphoxide
It is notable also that although the p-tolyl
lb reacted cleanly with methyl crotonate, the product 2d was a 151 mixture of diastereomers.
The conjugate addition of a range of sulphoxides to methyl crotonate was studied, and the results are shown in Table 2. Tbe addition of two n-butyl sulphoxides again showed that the t-butyl derivative lc reacted with much higher stereoselectivity was deprotonated
than the corresponding
using n-butyllithium
p-tolyl compound Id. The isopropyl sulphoxide
and it underwent a stereoselective
conjugate addition albeit in only
5823
Table Sulphoxide
a$-Unsaturated
2
Ester
Prod&’
Yieldb
? S
6””
2e,
64%
3 ‘: p-To1
2f,
/S
ad
dOMa
le
doMe
If
dOBut
68%
1.5 : 1 mixture of diastereomers
3 ? S B””
2g,
63%
2h,
53%
2i,
54%
h
? S B””
: lg
But/‘\
1.5 : 1 mixture of diastereomers
AOB,:
a. The n.m.r. (lH and 13C). i.r., and mass spectra of the products were fully consistent with the structures shown. b. Yields refer to stereoisomerically C.
n-Butyllithium
pure products.
was used to deprotonate the sulphoxide.
d. BHT = butylated hydroxy toluene ester (2,6-di-t-hutyl4methylphenyl).
moderate yield. Difficulties were encountered
with ethyl sulphoxide If because it gave substantial amounts of
acylation in the reaction with methyl crotonate under a variety of conditions.
However, changing to the t-butyl
ester gave the conjugate addition product 2h in 53% yield with only a trace of the acylated product. The methyl sulphoxide was even more problematic,
giving large amounts of acylation even with t-butyl crotonate.
Use of
the extremely hindered BHT ester13 did overcome the problem of competing acylation but the conjugate addition product 2i was formed as a 1S: 1 mixture of stereoisomers. These results show that the conjugate addition of Iithiated aIkyi sulphoxides can be achieved with high stereoselectivity. apparent, viz. a-substituted sulphoxides.
esters
The reaction appears to be fairly general but some limitations are
enoates cannot be used and good results have not yet been obtained for methyl
It is significant that t-butyl sulphoxides give high stereoselectivity
give very poor selectivity.
to o$unsaturated
This appears to be true also of some alkylations14J5
where-as p-tolyl derivatives and additions to
carbonyls,*4*r5*16 but the superior selectivity of the t-butyl derivatives does not seem to be widely appreciated, Moreover, the relative configuration stereochemistry
at sulphur and the a-carbon was the same in all cases in which the
of the product was unambiguously
determined,
as shown overleaf.
have sufficient data to suggest an explanation for this stereochemical
outcome.
At this stage we do not
5824
(i) Base
S
W
El”” ‘1 a
E
B”‘NS\/
(ii) ” E’ ” R
A
” E+ II= Dz017 * MeI14 . RCH@,‘6
, RCH=CHC@R Figure 1
The conjugate addition products described here should be useful synthetic intermediates, various transformations
is in progress.
predicated on the development
Of course the use of this method for enantioselective
of an efficient aysmmetric synthesis of the t-butyl sulphoxides,
and work on
synthesis is and progress in
this area will be reported shortly.
Acknowledgements We would like to thank Dr A. Redhouse for carrying out the X-ray crystal structure determination
and
Professor G. Procter for helpful discussions.
Representative Procedure A 1.4M solution of n-BuL.iin hexanes (15 ml, 21 mmol, 1.1 eq. ) was added to a cooled solution of diisopropylamine (2.94 ml, 2lmmo1, 1.1 eq.) in THF (75 ml) at O’C and the solution was stirred for 10 minutes. This solution was then cooled to -78’C and a precooled solution of t-hutyl phenethyl sulphoxide (la, 4 g, 19 mmol) in THF (19 ml) at -78-C was added dropwise via cannula. After 10 minutes a solution of methyl crotonate (2.83 ml, 26.7 mmol, 1.4 eq.) in THF (25 ml) at -78’C was added. After 3 minutes saturated aqueous ammonium chloride (40 ml) was added and the reaction mixture was allowed to warm to room temperature. The suspension was poured into water (100 ml) and extracted with dichloromethane (3 x 100 ml) and the combined extracts were dried over magnesium sulphate. The solvent was removed and the crude product was subjected to flash chromatography on silica (2:l petroleum ether:ethyl acetate) to give pure adduct 2b, 4.039 g, 68%. References K. Tomioka and K. Koga in “Asymmetric Synthesis”, ed. J.D. Morrison, Academic Press, New York, 1983, vol. 2, p. 201. 1. 2. For examples: D. Enders, K. Papadopoulos, B.E.M. Rendenbach, R. Appel, and F. Knoch, Tetrahedron Leff., 1986,27, 3491; M. Yamaguchi, K. Hasebe, S. Tamaka, and T. Minami, Tetrahedron Leff., 1986.27.959; E.J. Corey and R.T. Peterson, Tetrahedron Left., 1985.26, 5025. E.J. Corey, R. Naef, and F.J. Hannon, J. Am. Chem. Sot., 1986, 108, 7114; R.K. Dieter and M. Tokles, J. Am. Chem. 3. Sot., 1987, 109, 2040. L.L. Vasil’eva, V.I. Mel’nikova, E.T. Gainullina, and K.K. Pivnitskii, J. Org. Chem. USSR (Engl. Trunsl.), 1983.19, 4. 835; M.R. Binns, R.J. Goodridge, R.K. Haynes, and D.R. Ridley, Tetrahedron Leff., 1985, 26, 6381. D.H. Hua, J. Am. Gem. Sot., 1986, 108, 3835: D.H. Hua, J. Org. Chem., 1988, 53, 507. 5. L. Colombo, C. Gennari, G. Resnati, and C. Scolastico, J. Chem. Sot., Perkin Trans. I, 1981, 1284. 6. F. Matloubi and G. Solladie, Tefruhedron Leff., 1979,214l. 7. M.A. Buese and T.E. Hogan-Esch, Macromol., 1984, 17, 118. 8. 9. G. Solladie, G. Demailly, and C. Greek, J. Org. Chem., 1985.50, 1552. 10. Stereoisomer ratios are minimum values estimated from the n.m.r. spectia of the crude products. Minor isomers were not isolated but small amounts may have been present 11. The X-ray crystal structure determination was carried out by Dr. A. Redhouse. of this Department and full details will be published elsewhere. 12. The n.m.r. spectra of the products all showed some distinctive diagnostic features, and a full account of the analysis of the spectra, and the conformational analysis of the adducts will bc published elsewhere. 13. M.P. Cooke Jr., J. Org. Chem., 1986,51, 1637. 14. T. Durst, R. Viau, and M.R. McClory, J. Am. Chem. Sot., 1971,93, 3077. 15. M. Casey, I. Mukherjee, L. Nezhat, and A. Redhouse, unpublished results. 16. D.G. Farnum, T. Veysoglu, A.M. Carde, B. Duhl-Emswiler, T.A. Pancoast, T.J. Reitz. and R.T. Carde, Tetrahedron Leff., 1977.4009. 17. Y. Iitaka, A. Itai, N. Tomioka, Y. Kodama, K. Ichikawa, K. Nishihata, M. Nishio, M. Izumi, K. Doi, Bull. Chem. SOC. Jpn., 1986,59, 2801. (Received
in
UK 24
August
1988)
Letters,Vol.29,No.45,pp Great Britain
STEREOSELECTIVE
5821-5824,1988
CONJUGATE
CARBANIONS
ADDITIONS
0040-4039/88 $3.00 Pergamon Press plc
OF SULPHOXIDE
TO a$-UNSATURATED
+ -00
STABILISED
ESTERS
M. Casey,* A.C. Manage, and, in part, L. Nezhat Department of Chemistry and Applied Chemistry, University of Salford, Salford M5 4WT
Summaqv: The reaction of Iithiated a&l t-butyl sulphoxides with a&unsaturated
esters gives conjugate
addition products in good yield, with high stereoselectivity. Asymmetric
conjugate additions to a&unsaturated
carbonyl compounds have been the subject of
much attention, in keeping with the importance of these reactions in stereoselective stereoselectivity
has been achieved by incorporating
synthesis.
Excellent
a chiial auxiliaty into the electrophilic component1 and
more recently there have been notable successes using chiral nucleophiles, especially enolates2 and organocopper
reagents3
In the course of a wider survey of the use of lithiated sulphoxides as chiral nucleophiles surprised to find that the conjugate addition of a-sulphinyl has received little attention.
carbanions to a&unsaturated
we were
carbonyl compounds
The anions of ally1 sulphoxides add to enones with high regio- and stereoselectivity
and this reaction has been studied in detail by several groupsp culminating in elegant synthetic applications.5 Other sulphoxides
bearing a second anion stabilising group, such as a-arylthiosulphoxides6
esters,7 undergo less selective conjugate additions. sulphoxides
However, to our knowledge,
and a-sulphinyl
the use of simple alkyl
has not been reported, apart from conjugate additions to vinyl sulphoxides,*
and a mention of
conjugate addition to enoates as a side reaction to acylation.9 We have found that the anions derived from alkyl t-butyl sulphoxides
1 can be added to a$-
unsaturated esters, to give conjugate addition products 2 with very little competing acylation, and now present a preliminary report on the scope and stereoselectivity
of this reaction.
(i) LDA, THF. -78”
(iii)
H,O’
2
I
Reactions were carried out by adding precooled solutions of a&unsaturated alkyl sulphoxides
in THF at low temperatures
esters to lithiated t-butyl
and the results for a model sulphoxide la are shown in Table 1.
Addition to methyl acrylate proceeded smoothly giving the conjugate addition product 2a with no trace of competing stereoisomer
1,2-addition. subsequently
Moreover the n.m.r. of the crude product showed it to consist largely (2 5: l)lu of one assigned (see below) as 2a. The addition to methyl crotonate was also quite clean.
Although a trace of acylation product was observed a good yield of the conjugate addition product 2b was
5821
5822
Table 1 Sulphoxide
a$-Unsaturated
V S
Prod&
Yieldb
0
6””
la Ph
Ester
2a, 64%
&fdOMe
\ -A
OMe
z
>
0 B”tj’& Al
OMe
2b,
68%
2c,
63%
4,
38%
:
OMe Phj
JJdOMe Phd
OMe Ph’
/
‘:
O
3 0
(7
S
a. The n.m.r. (lH and
v
13C),ix., and mass spectra of the products were fully consistent with the structures shown.
b. Yields refer to stereoisomerically
obtained.
/
But’ Ph
OH
O
pure products.
The most notable feature of this addition is that it proceeded with high stereoselectivity,
diastereomer
being formed almost exclusively (2 10: 1). lo The relative stereochemistry
one
of the product was
determined by X-ray crystal structure analysis 11 and a computer generated drawing of the molecule is shown in Figure 1. The stereochemistry
of the other conjugate addition products was assigned by analogy with this
example and by detailed analysis of the n.m.r. spectra of the adducts. l2 Reaction of the lithiated sulphoxide with methyl cinnamate provided the conjugate addition product 2c with high stereoselectivity. In contrast, reaction with an unsaturated lactone 3 gave none of the desired conjugate addition product, a mixture of stereoisomers
of the acylated sulphoxide 4 being formed instead. Another limitation is that
addition to tiglate esters gave mixtures of products containing some acylation products, unreacted starting material, and only small amounts of the conjugate addition products. sulphoxide
It is notable also that although the p-tolyl
lb reacted cleanly with methyl crotonate, the product 2d was a 151 mixture of diastereomers.
The conjugate addition of a range of sulphoxides to methyl crotonate was studied, and the results are shown in Table 2. Tbe addition of two n-butyl sulphoxides again showed that the t-butyl derivative lc reacted with much higher stereoselectivity was deprotonated
than the corresponding
using n-butyllithium
p-tolyl compound Id. The isopropyl sulphoxide
and it underwent a stereoselective
conjugate addition albeit in only
5823
Table Sulphoxide
a$-Unsaturated
2
Ester
Prod&’
Yieldb
? S
6””
2e,
64%
3 ‘: p-To1
2f,
/S
ad
dOMa
le
doMe
If
dOBut
68%
1.5 : 1 mixture of diastereomers
3 ? S B””
2g,
63%
2h,
53%
2i,
54%
h
? S B””
: lg
But/‘\
1.5 : 1 mixture of diastereomers
AOB,:
a. The n.m.r. (lH and 13C). i.r., and mass spectra of the products were fully consistent with the structures shown. b. Yields refer to stereoisomerically C.
n-Butyllithium
pure products.
was used to deprotonate the sulphoxide.
d. BHT = butylated hydroxy toluene ester (2,6-di-t-hutyl4methylphenyl).
moderate yield. Difficulties were encountered
with ethyl sulphoxide If because it gave substantial amounts of
acylation in the reaction with methyl crotonate under a variety of conditions.
However, changing to the t-butyl
ester gave the conjugate addition product 2h in 53% yield with only a trace of the acylated product. The methyl sulphoxide was even more problematic,
giving large amounts of acylation even with t-butyl crotonate.
Use of
the extremely hindered BHT ester13 did overcome the problem of competing acylation but the conjugate addition product 2i was formed as a 1S: 1 mixture of stereoisomers. These results show that the conjugate addition of Iithiated aIkyi sulphoxides can be achieved with high stereoselectivity. apparent, viz. a-substituted sulphoxides.
esters
The reaction appears to be fairly general but some limitations are
enoates cannot be used and good results have not yet been obtained for methyl
It is significant that t-butyl sulphoxides give high stereoselectivity
give very poor selectivity.
to o$unsaturated
This appears to be true also of some alkylations14J5
where-as p-tolyl derivatives and additions to
carbonyls,*4*r5*16 but the superior selectivity of the t-butyl derivatives does not seem to be widely appreciated, Moreover, the relative configuration stereochemistry
at sulphur and the a-carbon was the same in all cases in which the
of the product was unambiguously
determined,
as shown overleaf.
have sufficient data to suggest an explanation for this stereochemical
outcome.
At this stage we do not
5824
(i) Base
S
W
El”” ‘1 a
E
B”‘NS\/
(ii) ” E’ ” R
A
” E+ II= Dz017 * MeI14 . RCH@,‘6
, RCH=CHC@R Figure 1
The conjugate addition products described here should be useful synthetic intermediates, various transformations
is in progress.
predicated on the development
Of course the use of this method for enantioselective
of an efficient aysmmetric synthesis of the t-butyl sulphoxides,
and work on
synthesis is and progress in
this area will be reported shortly.
Acknowledgements We would like to thank Dr A. Redhouse for carrying out the X-ray crystal structure determination
and
Professor G. Procter for helpful discussions.
Representative Procedure A 1.4M solution of n-BuL.iin hexanes (15 ml, 21 mmol, 1.1 eq. ) was added to a cooled solution of diisopropylamine (2.94 ml, 2lmmo1, 1.1 eq.) in THF (75 ml) at O’C and the solution was stirred for 10 minutes. This solution was then cooled to -78’C and a precooled solution of t-hutyl phenethyl sulphoxide (la, 4 g, 19 mmol) in THF (19 ml) at -78-C was added dropwise via cannula. After 10 minutes a solution of methyl crotonate (2.83 ml, 26.7 mmol, 1.4 eq.) in THF (25 ml) at -78’C was added. After 3 minutes saturated aqueous ammonium chloride (40 ml) was added and the reaction mixture was allowed to warm to room temperature. The suspension was poured into water (100 ml) and extracted with dichloromethane (3 x 100 ml) and the combined extracts were dried over magnesium sulphate. The solvent was removed and the crude product was subjected to flash chromatography on silica (2:l petroleum ether:ethyl acetate) to give pure adduct 2b, 4.039 g, 68%. References K. Tomioka and K. Koga in “Asymmetric Synthesis”, ed. J.D. Morrison, Academic Press, New York, 1983, vol. 2, p. 201. 1. 2. For examples: D. Enders, K. Papadopoulos, B.E.M. Rendenbach, R. Appel, and F. Knoch, Tetrahedron Leff., 1986,27, 3491; M. Yamaguchi, K. Hasebe, S. Tamaka, and T. Minami, Tetrahedron Leff., 1986.27.959; E.J. Corey and R.T. Peterson, Tetrahedron Left., 1985.26, 5025. E.J. Corey, R. Naef, and F.J. Hannon, J. Am. Chem. Sot., 1986, 108, 7114; R.K. Dieter and M. Tokles, J. Am. Chem. 3. Sot., 1987, 109, 2040. L.L. Vasil’eva, V.I. Mel’nikova, E.T. Gainullina, and K.K. Pivnitskii, J. Org. Chem. USSR (Engl. Trunsl.), 1983.19, 4. 835; M.R. Binns, R.J. Goodridge, R.K. Haynes, and D.R. Ridley, Tetrahedron Leff., 1985, 26, 6381. D.H. Hua, J. Am. Gem. Sot., 1986, 108, 3835: D.H. Hua, J. Org. Chem., 1988, 53, 507. 5. L. Colombo, C. Gennari, G. Resnati, and C. Scolastico, J. Chem. Sot., Perkin Trans. I, 1981, 1284. 6. F. Matloubi and G. Solladie, Tefruhedron Leff., 1979,214l. 7. M.A. Buese and T.E. Hogan-Esch, Macromol., 1984, 17, 118. 8. 9. G. Solladie, G. Demailly, and C. Greek, J. Org. Chem., 1985.50, 1552. 10. Stereoisomer ratios are minimum values estimated from the n.m.r. spectia of the crude products. Minor isomers were not isolated but small amounts may have been present 11. The X-ray crystal structure determination was carried out by Dr. A. Redhouse. of this Department and full details will be published elsewhere. 12. The n.m.r. spectra of the products all showed some distinctive diagnostic features, and a full account of the analysis of the spectra, and the conformational analysis of the adducts will bc published elsewhere. 13. M.P. Cooke Jr., J. Org. Chem., 1986,51, 1637. 14. T. Durst, R. Viau, and M.R. McClory, J. Am. Chem. Sot., 1971,93, 3077. 15. M. Casey, I. Mukherjee, L. Nezhat, and A. Redhouse, unpublished results. 16. D.G. Farnum, T. Veysoglu, A.M. Carde, B. Duhl-Emswiler, T.A. Pancoast, T.J. Reitz. and R.T. Carde, Tetrahedron Leff., 1977.4009. 17. Y. Iitaka, A. Itai, N. Tomioka, Y. Kodama, K. Ichikawa, K. Nishihata, M. Nishio, M. Izumi, K. Doi, Bull. Chem. SOC. Jpn., 1986,59, 2801. (Received
in
UK 24
August
1988)