Applications of the Baylis-Hillman reaction in the synthesis of coumarin derivatives

Musa, Musiliyu Ayodele (2003) Applications of the Baylis-Hillman reaction in the synthesis of coumarin derivatives. PhD thesis, Rhodes University.

[img]
Preview
Text
MUSA-PhD-TR03-74.pdf

1403Kb

Abstract

The reaction of specially prepared salicylaldehyde benzyl ethers with the activated alkenes, methyl acrylate or acrylonitrile, in the presence of the catalyst, DABCO, has afforded Baylis-Hillman products, which have been subjected to conjugate addition with either piperidine or benzylamine. Hydrogenolysis of these conjugate addition products in the presence of a palladium-on-carbon catalyst has been shown to afford the corresponding 3-substituted coumarins, while treatment of O-benzylated Baylis-Hillman adducts with HCl or HI afforded the corresponding 3-(halomethyl)coumarins directly, in up to 94%. The 3-(halomethyl)coumarins have also been obtained in excellent yields (up to 98%) and even more conveniently, by treating the unprotected Baylis-Hillman products with HCl in a mixture of AcOH and Ac2O, obtained from tert-butyl acrylate and various salicylaldehydes. The generality of an established route to the synthesis of coumarins via an intramolecular Baylis-Hillman reaction, involving the use of salicylaldehyde acrylate esters in the presence of DABCO, has also been demonstrated. Reactions between the 3-(halomethyl)coumarins and various nitrogen and carbon nucleophiles have been shown to proceed with a high degree of regioselectivity at the exocyclic allylic centre to afford 3-substituted coumarin products. The electronimpact mass spectra of selected coumarin derivatives have been investigated using high-resolution and B/E linked scan data. Fragmentation pathways have been proposed and fragmentation modes associated with different coumarin-containing analogues have been compared. A series of coumarin-containing analogues of ritonavir (a clinically useful HIV-1 protease inhibitor) have been prepared and characterized. The synthetic approach has involved the coupling of coumarin derivatives with a hydroxyethylene dipeptide isostere to afford ritonavir analogues containing coumarin termini. An interactive docking procedure has been used to explore the docking of ritonavir and a coumarincontaining analogue into the enzyme active site.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Heterocyclic compounds, Coumarins
Subjects:Q Science > QD Chemistry
Divisions:Faculty > Faculty of Science > Chemistry
ID Code:2319
Deposited By: Mrs Carol Perold
Deposited On:09 Dec 2011 09:17
Last Modified:06 Jan 2012 16:22
214 full-text download(s) since 09 Dec 2011 09:17
214 full-text download(s) in the past 12 months
More statistics...

Repository Staff Only: item control page