There is a prevailing demand for versatile methodology that enables the synthesis of structurally diverse aromatic/heteroaromatics using commercially available/easily prepared substrates that uses mild reagents and conditions. Heteroaromatics can be prepared using a de-novo approach that employs [4+2] cycloaddition reactions of heteroaromatic dienes (e.g. pyrones, diazines) with alkyne dienophiles. Subsequent elimination of small gaseous molecules afford functionalised benzenoid ring systems for natural product synthesis or drug discovery applications (Fig. 1a & b). However, the widespread use of this type of benzannulation methodology for synthetic applications is currently restricted by the limited range of commercially available pyrone/diazine substrates and their relatively poor reactivity in these type of [4+2] cyclisation reactions. We now report development of novel methodology for the synthesis of a range of protected N-oxypyrroles that function as reactive heterodienes for [4+2] cycloaddition reactions with a range of alkyne dienophiles. The resultant bicyclic adducts can be isolated and characterised and readily undergo cheletropic elimination of nitroxyl to afford substituted aromatic scaffolds in good yields (Fig. 1c). These N-oxypyrrole dienes demonstrate significantly higher reactivity towards this type of Diels-Alder reaction when compared to other heteroaromatic dienes in common usage, allowing for their reaction with relatively unreactive dienophiles (e.g. methyl propiolate) in short reaction times. In addition to the use of N-oxypyrroles as dienes, the analogous N-oxyimidazoles have been shown to react with arynes to afford their corresponding isoquinolines in good yields (Fig. 1d).

[4+2] Cycloaddition methodology for the synthesis of functionalised aromatic scaffolds

2019 Fall National Meeting

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