A radical approach towards the synthesis of fused nitrogen heterocycles
A literature review of the chemistry of homolytic aromatic substitution is presented with particular emphasis to the formation of fused heterocyclic systems. A series of five-membered spirocyclic 5-azaoxindole-ring systems have been synthesised by generating an alkyl radical that underwent an intramolecular radical cyclisation at the 3-positon of a pyridine ring and was followed by oxidation giving rise to a mix of fused pyridine ring systems. However, numerous problems were encountered with this investigation, not least the stability of the alpha brominated carbonyl radical precursor, consequently an alternative protocol was investigated. Bromine was therefore introduced at the 3-position of the heteroaromatic ring. Generation of the radical followed by a 1,5 radical translocation, an intramolecular radical cyclisation followed by oxidation furnished the required fused ring systems. Synthesis of the 5-azaoxindole systems was also shown to proceed in good yield in the presence of a 2-fold excess of AIBN and only poorly when 1.2eq was used using this method. The methodology was successfully extended demonstrating that cyclisation of an alkyl radical is regioselective at the 2-positoin of the pyridine over the 4-position providing access to a variety of 4-azaoxindole systems. It was also shown that radical cyclisation into the pyrimidine ring is a feasible process although in rather poor yield. As a final challenge to probe the generality and utility of homolytic aromatic substitution into heterocyclic ring systems six-membered fused ring systems were investigated. This investigation resulted in the formation of a range of six-membered nitrogen heterocycles in excellent yield and provided access to the core ring system of the natural alkaloid sesbanine.