Diels-Alder reactions of α,β-unsaturated thioesters and α,β-unsaturated selenoesters

Article abstract of DOI:10.1055/s-1998-1738

α,β-Unsaturated thioesters and selenoesters serve as dienophiles in Diels-Alder reactions with a variety of 1,3-dienes. Good levels of regioselectivity are obtained with unsymmetrical dienes when Lewis acid promoters are used. Thioesters and selenoesters

Full text of DOI:10.1055/s-1998-1738

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Diels-Alder Reactions of α,β-Unsaturated Thioesters and α,β-Unsaturated Selenoesters
Chang-Ho Byeon, Cheng-Yi Chen, David A. Ellis, David J. Hart* and Jing Li
Department of Chemistry, The Ohio State University, 100 W. 18th Ave. Columbus, Ohio 43210, USA
Received 14 November 1997
Abstract: α,β-Unsaturated thioesters and selenoesters serve as
dienophiles in Diels-Alder reactions with a variety of 1,3-dienes. Good
levels of regioselectivity are obtained with unsymmetrical dienes when
Lewis acid promoters are used. Thioesters and selenoesters are more
reactive than the corresponding methyl esters based on competition
experiments with cyclopentadiene.
Only a few examples of Diels-Alder reactions in which α,β-unsaturated
1-5
thioesters serve as dienophiles have been reported and the use of α,β-
unsaturated selenoesters as dienophiles has not been described. During
the course of two alkaloid total syntheses, we found α,β-unsaturated
thioesters to be useful in situations where the corresponding esters
3,4
lacked reactivity needed to participate in Diels-Alder reactions.
Because of their potential for use in synthesis and the limited attention
they have received to date, we have conducted a systematic study of
Diels-Alder reactions of selected α,β-unsaturated thioesters and related
α,β-unsaturated selenoesters. The results are reported herein.
Thioesters and selenoesters 1-4 were selected for study and prepared as
follows. Treatment of crotonyl chloride with one equivalent of
thiophenol or selenophenol in the presence of pyridine gave 1 (45%)
and 2 (48%), respectively. Similar treatment of methyl fumaroyl
o
chloride with thiophenol or selenophenol provided 3 (mp 70-71 C) and
o
4 (mp 62-65 C), in 46% and 45% yields, respectively. Cycloaddition
reactions of these dienophiles were examined with isoprene (5),
piperylene
cyclopentadiene (8). Each cycloaddition was examined under three
conditions: thermal, using a soluble Lewis acid promoter (EtAlCl or
(6),
2-trimethylsiloxy-1,3-butadiene
(7),
and
2
TiCl ), and using a solid supported Lewis acid promoter (SiO -
4
2
6
Et AlCl). The results are documented in Tables 1-4.
2
Table 1 shows that thermal reactions between 1-4 and isoprene
7-8
(Condition A) show little regioselectivity as expected.
Regioselectivity improves to useful levels upon use of soluble Lewis
7
acid promoters (Condition B). Most notable is that the thioester and
selenoester groups in 3 and 4 direct the course of the cycloaddition
9
rather than the carbomethoxy group. Finally, the solid supported Lewis
acid (Condition C) provides useful levels of reactivity with crotonic acid
derivatives 1 and 2, but is ineffective with fumaric acid derivatives 3
and 4.
Table 2 shows that thermal reactions between 1-4 and piperylene afford
a mixture of regioisomeric endo and exo cycloadducts. As with
isoprene, the use of either soluble or solid supported Lewis acids
improves both regioselectivity and stereoselectivity with dienophiles 1
and 2. Dienophiles 3 and 4 do not respond well to Lewis acids, however,
as four isomeric cycloadducts are obtained.
10
cycloadditions. Also, the solid supported Lewis acid (SiO -Et AlCl)
2 2
destroyed diene 7 and no cycloadducts were obtained.
Table 4 indicates that thermal reactions of cyclopentadiene with 1-4
show little endo-exo selectivity, but the situation improves in the
12
presence of Lewis acid promoters. For example, titanium tetrachloride
improves selectivity to useful levels with all four dienophiles, whereas
Table 3 shows that thermal and soluble Lewis acid promoted reactions
of 1 and 2 with 2-trimethysiloxy-1,3-butadiene give good yields of
cyclohexanones with excellent regioselectivity after a hydrolytic work-
up. On the other hand dienophiles 3 and 4 show good regioselectivity
only in the presence of soluble Lewis acid promoters. Once again, the
thioester and selenoester groups direct the regiochemical course of the
SiO -Et AlCl improves selectivity in reactions of 1 and 2, but is
2
2
ineffective in reactions of 3 and 4.
11
One feature of thioesters and selenoesters as dienophiles is that they are
more reactive than normal esters. For example, when a 10-fold excess of
o
dimethyl fumarate (9) and dithioester 10 (mp 135-136 C) were allowed

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Another useful feature of thioesters and selenoesters as dienophiles is
that the chemistry of these functional groups differs from the chemistry
of esters. This can be put to good use. For example in a synthesis of
himbacine, a thioester cycloaddition was followed by its reduction to an
4
alcohol using RaNi, without reduction of an appended lactone. To
further demonstrate the utility of this difference in reactivity, the
cycloadduct derived from isoprene and selenoester 4 was treated with
tri-n-butyltin hydride and AIBN to provide keto ester 15 in 56% yield
14
along with 16% of aldehyde 16. This establishes 4 as a reverse
15
regiochemistry acrylate equivalent in Diels-Alder reactions. Finally,
treatment of the cycloadduct derived from isoprene and thioester 3 with
sodium borohydride in ethanol, gave hydroxy ester 17 in 74% yield,
establishing another reverse regiochemistry equivalent. It is our hope
that these studies will encourage others to use thioesters and
selenoesters as dienophiles in appropriate situations.
Acknowledgement. We thank the National Institutes of Health for
generous support.
References and Notes
1.
2.
Wu, H.; Pan, K J. Chem. Soc., Chem. Commun. 1987, 898.
Wladislaw, B.; Marzorati, L.; Gruber, J. Phosphorus, Sulfur,
Silicon and Related Elements 1991, 59, 185.
3.
4.
Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840.
Hart, D. J.; Wu. W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
117, 9369. Hart, D. J.; Li, J.; Wu, W.-L.; Kozikiwski, A. P. J. Org.
Chem. 1997, 62, 5023.
5.
6.
Witter, D. J.; Vederas, J. C. J. Org. Chem. 1996, 61, 2613.
Cativiela, C.; Fraile, J. M.; Garcia, J. I.; Mayoral, J. A.; Pires, E.;
Royo, A. J.; Figueras, F.; de Menorval, L. C. Tetrahedron 1993,
49, 4073.
7.
8.
Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436. Fray, G. I.;
Robinson, R. J. Am. Chem. Soc. 1961, 83, 249. Lutz, E. F.; Bailey,
G. M. J. Am. Chem. Soc. 1964, 86, 3899. Inukai, T.; Kojima, T. J.
Org. Chem. 1966, 31, 2032.
The major product (p) from each reactant pair was isolated and
1
13
characterized by H and C NMR, IR and MS. The presence of
minor cycloadducts (m) was inferred from signals in the NMR
spectra of purified product mixtures [for example the allylic
methyl group (reactions of 1-2) and the methines adjacent to the
thioester and/or ester groups (reactions of 1-4)]. The
regiochemistry in the reactions of 1 and 2 with 5 are based on the
7
well-known behavior of crotonate-isoprene cycloadditions.
13 13
INADEQUATE ( C- C correlation) experiments were used to
to compete for a limiting amount of cyclopentadiene, cycloadduct 12
was obtained along with only trace amounts of 13. A competition
establish regiochemistry in the cycloaddition between 3 and 5.
9.
For another fumaric acid derivative that shows selective
complexation with a Lewis acid see Maruoka, K.; Saito, S.;
Yamamoto, H. J. Am. Chem. Soc. 1992, 114, 1089.
o
between dimethyl fumarate and diselenoester 11 (mp 121-122 C) also
13
gave 14 and only a trace of 13.
10. Pure samples of a and b were obtained from reactions involving 1
and 2. Their stereochemistry was assigned on the basis of the
coupling constants of the methine adjacent to the carbonyl group
[dd (J = 10, 5 Hz) for a and t (J = 10 Hz) for b]. The third isomer
1
(stereochemistry unknown) was detectable in the H-NMR of the
purified mixture. Product ratios in reactions of 3 and 4 were
determined by integration of their respective methyl doublets,
which were clearly separated (δ 0.97, 1.17, 0.90 and 1.05 for a-d
respectively). Pure samples of a and b were isolated and their
structures and stereochemistry assigned using a combination of
13 13
coupling constant data, INADEQUATE ( C- C correlation)

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experiments, iodolactonization experiments, and chemical
correlation with piperylene-dimethyl fumarate cycloadducts.
mercurilactonization reaction (HgCl , CaCO , CH CN, H O)
2 3 3 2
established the structures of the endo adducts from 1 and 3. The
carboxylic acid derived from the exo-adduct with 3 was isolated
and characterized when this sequence was applied to a mixture of
endo and exo cycloadducts.
11. Pure samples of the major products (p) from each of the four
1
13
cycloaddition pairs were isolated and characterized by H and
C
NMR, IR and MS. Signals due to minor cycloadducts (m) were
not apparent in the reactions of 1 and 2. They were clearly present
13. For relevant relative rate studies see Sauer, J. Angew. Chem., Int.
Ed. Engl. 1966, 5, 211. Sauer, J. Angew. Chem., Int. Ed. Engl.
1967, 6, 16.
in the NMR spectra (CO Me) of purified reaction products
2
13 13
derived from 3 and 4. INADEQUATE ( C- C correlation)
experiments were used to establish regiochemistry in the
14. Pfenninger, J.; Heuberger, C.; Graf, W. Helv. Chim. Acta 1980, 63,
cycloaddition between 3 and 7.
2328.
12. Pure samples of all products were isolated except for the exo-
15. For another reverse polarity acrylate equivalent see Kakushima,
adduct in the reaction of 3.
A
one-pot hydrolysis-
M.; Espinosa, J.; Valenta, Z. Can. J. Chem. 1976, 54, 3304.