An investigation of the preparation of heterocyclic ring systems via intramolecular nucleophilic aromatic substitution
thesisposted on 2012-09-26, 13:39 authored by Philip H.G. Smith
Heterocyclic synthesis via processes involving single electron transfer, namely aromatic SRN1 ,reactions and copper metal- and cuprous halide-promoted substitutions have been investigated. The cyclisation step in all the 'syntheses is effected by an intramolecular aromatic nucelophilic substitution on a halogen atom which is ortho to the side chain bearing the nucleophilic species (generally an amide or thioamide moiety). The process of entrainment has been shown to be a valuable technique for effecting reactions performed' under SRN1 conditions. The mechanisms of, and the mechanistic relationships between the substitution processes, were investigated using well documented diagnostic probes for the SRN1 reaction and by conducting series of experiments on simple reaction systems whose behaviour under SRN1 conditions was already known. Ring systems prepared by the methods noted above include benzoxazoles, benzothiazoles, 1 ,3-benzothiazines, indoles and a tricyclic system. Attempts to prepare seven-membered heterocycles by increasing the length of the side chain proved unsuccessful. When the side chain bears a carbonyl function adjacent to the aromatic ring, an intramolecular SNAr reaction takes place and cyclisation of N-(2-haloaroyl)-N'-phenylthioureas occurred under mild conditions. Quinazolinones and a 1 ,3-benzothiazinone have been synthesised in this manner which appears to have little precedent in the chemical literature. The preparation of seven-membered heterocycles by an SNAr cyclisation proved fruitless extension of the side chain length by one carbon atom (effected by the preparation of an N-cinnamoyl-N-phenylthiourea) resulted in the cyclisation of the side chain. Reaction of certain of the N,N-disubstituted thioureas with copper (1) iodide results in the formation of 2-halobenzanilides by a novel rearrangement.