Medicinally Relevant Modification of the Isoquinoline-1,3-dione Scaffold via Metal-Free Arylation and Fluorination of Diazo Homophthalimides­ in Brønsted Acids

Abstract

Protonation of 4-diazoisoquinoline-1,3(2H,4H)-diones in Brønsted acids gives rise to diazonium cations that can be trapped with arenes to give 4-arylisoquinoline-1,3(2H,4H)-diones (homophthalimides). This provides a new, metal-free approach to 4-aryltetrahydroisoquinolines (obtainable from respective homophthalimides by reduction). Similarly, a fluorine atom can be introduced by trapping the diazonium cation with HF. This led to the preparation of the first examples of 4-monofluoro-substituted isoquinoline-1,3-diones (as well as their 4-bromo-4-fluoro and 4-chloro-4-fluoro variants), important carboxylic acid isosteres on their own and precursors of useful 4-fluorotetrahydroisoquinoline building blocks.

Key words

homophthalimides - diazo compounds - arylation - Friedel–Crafts reaction - monofluorination - fluorohalogenation - Brønsted acids - isoquinoline-1,3(2H,4H)-dione

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