Transition Metal‐Free Synthesis of 3‐Aryl‐4‐Cyano Isocoumarin Derivatives with 2‐Cyanomethyl Aroyl Fluorides and Their Applications

Synthesis of 3-aryl-4-cyano isocoumarins from 2-cyanomethyl aroyl fluorides was investigated. After deprotonation of cyanomethylene group in aroyl fluorides, sequential acyl substitution and intramolecular cyclization provided isocoumarins in excellent to moderate yields. Synthetic applications of 3-aryl-4-cyano isocoumarins to more complex isocoumarins or isoquinolinones through a one-step reaction were also demonstrated, enabling access to structurally diverse heterocycles of potential interest.

Abstract

We demonstrated a sequential synthetic approach to prepare 3-aryl-4-cyano isocoumarins using 2-cyanomethyl aroyl fluorides as starting materials. The reaction was initiated by deprotonation of the cyanomethyl group with Hünig's base, followed by acyl substitution and intramolecular cyclization, which provided the expected isocoumarin derivative in excellent to moderate yields. To expand the utility of the obtained isocoumarins, further transformations were investigated, including the conversion of isocoumarins into isoquinolinones under a simple, one-step reaction. Our methodology enables the efficient synthesis of 3-aryl-4-cyano isocoumarins, which are structurally related to scaffolds of interest in medicinal chemistry and biological studies.

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