Barton esters for initiator-free radical cyclisation with heteroaromatic substitution and anti-cancer evaluation of benzo[e][1,2,4]triazin-7-ones

Abstract

Chapter 1 provides a general introduction to Chapters 2-5. Homolytic aromatic substitution routes to alicyclic ring-fused azoles and diazoles is reviewed. A review of recent literature using the COMPARE program of the National Cancer Institute (NCI, USA) to elucidate anti-cancer activity of small heterocyclic molecules is presented. Chapter 2 describes S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) facilitating the first examples of efficient radical cyclisation with (hetero)aromatic substitution via Barton ester intermediates. Cyclopropyl and alkyl radicals allow access to five, six and seven-membered alicyclic-ring fused heterocycles with and without an additional fused cyclopropane, including the skeleton of the anti-cancer agent, cyclopropamitosene, expanded, and diazole analogues. Radical initiators are not required for cyclisation from carboxylic acid precursors. For constrained cyclisations such as the seven-membered cyclopropyl radical aromatic substitution onto indole, the Bu3SnH-mediated reaction was found to give higher yields, and X-ray crystal structure of the adduct, 1,1a,2,3,4,10b-hexahydrocyclopropa[3,4]azepino[1,2-a]indole-10-carbaldehyde was obtained. Chapter 3 describes a new synthetic use of Barton esters, as precursors for one-pot initiator-free cascade/tandem reactions. The tandem reaction involves intermolecular addition of alkyl radicals onto activated terminal (monosubstituted) alkynes followed by intramolecular substitution of vinyl radicals onto indoles. Investigations into the use of disubstituted alkynes (with two different substituents) are also presented with X-ray crystal structures of substitution products demonstrating the selectivity of the radical addition onto the alkyne. Chapter 4 describes preliminary investigations into elucidating the anti-cancer activity of diphenylbenzo-[e][1,2,4]triazin-7-one (compounds) supplied by the group of Prof. Panayiotis A. Koutentis (University of Cyprus) using cytotoxicity evaluation of the parent compound (1,3-diphenylbenzo-[e][1,2,4]triazin-7-one) at the NCI, and MTT assays of analogues. The COMPARE program established a very strong correlation with naturally occurring antibiotics. Chapter 5 is a comprehensive description of synthetic and tissue culture procedures carried out.