The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:rhodes/vital:4556 |
| Date | January 2001 |
| Creators | Nocanda, Xolani Wittleton |
| Publisher | Rhodes University, Faculty of Science, Chemistry |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis, Doctoral, PhD |
| Format | 202 leaves, pdf |
| Rights | Nocanda, Xolani Wittleton |
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