Tandem Diels-Alder/ene reactions

Article abstract of DOI:10.1021/ol048847d

(Chemical Equation Presented) The reactions of unsaturated aldehydes and triene 3 afford adducts via a tandem Diels-Alder/ene reaction.

Full text of DOI:10.1021/ol048847d

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3115-3117
Tandem Diels−Alder/Ene Reactions
George A. Kraus* and Junwon Kim
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
gakraus@iastate.edu
Received June 17, 2004
ABSTRACT
The reactions of unsaturated aldehydes and triene 3 afford adducts via a tandem Diels−Alder/ene reaction.
Tandem reactions have become a powerful tool for the
synthetic chemist.1 They often enable the generation of
multiple stereogenic centers in a single operation. We have
recently been interested in tandem Diels-Alder/radical
cyclizations.2 To study these reactions sequentially, we
attempted to generate bromo aldehyde 1 by a Diels-Alder
reaction between 2-bromoacrolein (2)3 and diene 3. The
reaction of 2 with 3 did not yield 1 either by a thermal or a
Lewis acid-catalyzed pathway. The product, alcohol 4, was
generated as a single diastereomer by a tandem Diels-Alder/
ene reaction.4 After searching the literature, we believe the
examples described herein represent the first examples of
this tandem reaction. Heathcock, in his elegant synthesis of
Daphniphyllum alkaloids, employed a hetero-Diels-Alder/
ene sequence.5 There are also a few examples of tandem
Diels-Alder/Diels-Alder reactions and tandem ene/ene
reactions.6
The stereochemistry of bromo alcohol 4 was determined
by chemical and spectral methods. Since bromo alcohol 4
resisted epoxide formation under the conventional condi-
tions,7 the alcohol was assumed to be syn to the bromine.
NOESY NMR experiments showed strong interactions
between the carbinol hydrogen and the methyl of the
isopropenyl group, indicating that the isopropenyl group was
syn to the methine. No NOE interaction was observed
between the carbinol hydrogen and the methine at the ring
juncture. The structure of the adduct from 2,5-dihy-
drothiophene-3-carboxaldehyde and 3 was determined by
X-ray crystallography. The product stereochemistries are
consistent with an endo-selective Diels-Alder reaction
followed by an ene reaction via a chairlike conformation.
To better understand the scope and limitations of this
reaction, we reacted several substituted acroleins with trienes.
(1) Neuschutz, K.; Velker, J.; Neier, R. Synthesis 1998, 227. (b) Parsons,
P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Bunce, R.
A. Tetrahedron 1995, 51, 13103. (d) Winkler, J. D. Chem. ReV. 1996, 96,
167-76.
(2) Kraus, G. A.; Kim, J. W. Tetrahedron Lett. 2004, 45, 1457-1459.
(3) Yuan L. Chow.; Bert H. Bakker. Can. J. Chem. 1982, 60, 2268-73.
(4) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17,
976. Snider, B. B. Acc. Chem. Res. 1980, 13, 426.
(5) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. J. Am. Chem. Soc.
1988, 110, 8734-6
(6) Tandem Diels-Alder/Diels-Alder reactions: Spino, S.; Crawford,
J.; Bishop, J. J. Org. Chem. 1995, 60, 844-851. Tandem ene/ene
reactions: Snider, B. B.; Deutsch, E. A. J. Org. Chem. 1983, 48, 1822-
29.
(7) Avery, M. A.; Detre, G.; Yasuda, D.; Chao, W. R.; Tanabe, M.;
Crowe, D.; Peters, R.; Chong, W. K. M. J. Med. Chem. 1990, 33, 1852.
Bednarski, P. J.; Nelson, S. D. J. Med. Chem. 1989, 32, 203.
10.1021/ol048847d CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/05/2004

Table 1.
The results of this research are illustrated in Table 1.
Although the reaction of 2 with 3 could be conducted using
either thermal or Lewis acid-catalyzed conditions, the
reactions with less reactive aldehydes needed to be conducted
using Lewis acid catalysis. It is clear from the results in Table
1 that the tandem reaction is general for substituted acroleins.
Interestingly, 2-methylbutenal, 2,5-dihydrothiophene-3-
carboxaldehyde,8 and cyclopentene carboxaldehyde react
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Org. Lett., Vol. 6, No. 18, 2004

with 3 to afford a single stereoisomer.9 The adduct with
acrolein is a 3:2:1 mixture of diastereomers. The adduct
derived from methacrolein is a 2:1 mixture of diastereomers.
We attempted to extend this reaction to unsaturated ketones.
Unfortunately, the reaction of 3-bromobuten-2-one with
triene 3 afforded only the Diels-Alder adduct 5 in 81%
yield.
should be compatible with a wide variety of trienes and
unsaturated aldehydes.
Acknowledgment. We thank Iowa State University for
partial support.
Supporting Information Available: Spectra NMR and
CMR spectra for compounds in Table 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048847D
(8) Huckabee, B. K.; Stuk, T. L. Synth. Commun. 2001, 31, 1527-1530.
(9) General Procedure for Tandem Diels-Alder/Ene Reaction. To a
0 °C solution of R,â-unsaturated aldehyde (1.1 mmol) in Et2O (3.5 mL)
was added BF3‚OEt2 (1.1 mmol) and the mixture stirred for 10 min at 0 °C
(in the case of Et2AlCl, it was added to aldehyde at -78 °C and stirred for
10 min at -78 °C). To the resulting yellow solution was added via cannula
a solution of triene (1 mmol) in Et2O (1. mL plus 0.5 mL rinse). After 1 h
at 0 °C, the reaction was warmed to rt and further stirred for 6-19 h
(monitored by TLC). The reaction was quenched by the addition of saturated
aqueous NH4Cl (3 mL) and extracted by CH2Cl2. The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified via flash column chromatography to give the adduct.
The tandem Diels-Alder/ene reactions create up to five
stereogenic centers in a single operation. The bicyclic alcohol
derived from dimethylacrolein contains the skeleton of the
eremophilane sesquiterpenes. The mild reaction conditions
Org. Lett., Vol. 6, No. 18, 2004
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