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Access to fused nitrogen heterocycles via DielsAlder reactions of pyrrole with maleimide
Dr. Wayland E.
1
Noland ;
Dr. Venkata Srinivasarao
1
Narina ;
Matthew
1
Epplin
1 Chemistry Department, College of Science and Engineering, University of Minnesota – Twin Cities, Minneapolis, MN
Abstract
Nitrogen heterocyclic chemistry is attractive because of its potential impact in
the form of both natural and synthetic products. Fused pyrrole rings in particular
have shown the potential for anti-cancerous activity upon placement in the
human body. Recently, many have been interested in increasing the efficiency of
this family of reactions in order to not only create molecules with biological
activity, but create them with high yield for potential industrial use. Herein, we
report the synthesis of a fused pyrrole diene for further cyclization with
maleimide with the intention of forming a biologically active Diels-Alder adduct
in high yield. Decarboxylation with sodium hydroxide to form the fused ketone
has been performed in good yield. This scheme can be applied generally to form
useful diene products from cheap and plentiful starting materials that have the
potential to create a positive medical effect. Future efforts will be focused on
fused rings of varying size as well as the addition of substituted maleimide
derivatives using a similar methodology described.
Synthesis of Diels Alder Adduct
Fused Ketone Synthesis
Conclusions
• Synthesis of the fused ketone was achieved in six steps using
trichloroacetic acid as the starting reagent
• Yield of the Dieckmann condensation of the diester was
improved through the use of a more polar aprotic solvent in
DMF
• Once the Wittig and Diels-Alder reactions are performed and
the final product is purified and characterized, it will be
subjected to the appropriate analysis in search of significant
biological activity
Future Work
Background
• Completion of reduction and Diels-Alder reactions to form final
fused pyrrole
• Pyrrole and indole heterocycle derivatives have shown
potential for biological activity
• Our group has previously synthesized indoles from 2vinylpyrroles that have shown sufficient biological activity to
begin human tumor cell line screening
• Synthesis of fused ketones with differing ring sizes
• Further Diels-Alder reactions using functionalized maleimides
as the dienophile
• Decarboxylation with base created a mixture of the ketone
and diacid
Reduction and Diels Alder Reactions
• Showed activity against melanoma, breast cancer, and
leukemia upon testing
• This experiment was focused on the synthesis and
optimization of one fused pyrrole ring, taking yield and
reagent cost into strong consideration
Bibliography
1.) Noland, W.E., et al. Access to Indoles via Diels-Alder Reactions of 2-Vinylpyrroles with
Maleimides. Journal of Heterocyclic Chemistry, 2009; 46: 1154-1176.
2.) Noland, W.E., et al. Access to Indoles via Diels-Alder Reactions of 5-Methylthio-2vinylpyrroles with Maleimides. Journal of Heterocyclic Chemistry, 2013; 50: 795-808.
3.) Bit, R.A., et al. A Dieckmann/ring expansion approach to tetrahydropyrido- and
tetrahydroazepino-[1,2-a] indoles. Tetrahedron, 1991; 47 (26): 4645-4664.
4.) Wallace, D.M., et al. Rational teraarylporphyrin syntheses: tetraarylporphyrins from the
MacDonald Route. Journal of Organic Chemistry, 1993; 58: 7245-7257.
5.) Aldabbagh, F.W., et al. Oxidative Radical Cyclisations onto Imidazoles and Pyrroles using
Bu3SnH. Tetrahedron, 1999; 55: 8111-8128.
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