A Convenient Synthesis of Iguratimod‐Amine Precursor via NHC‐Catalyzed Aldehyde‐Nitrile Cross Coupling Reaction

A protocol for the synthesis of iguratimod‐amine precursor has been developed using N‐heterocyclic carbene (NHC)‐catalyzed aldehyde‐nitrile cross coupling reaction with overall atom efficiency of 71 %. The first step involves a nucleophilic aromatic substitution (S N Ar) of 1‐chloro‐4‐methoxy‐2‐nitrobenzene ( 1 ) with phenol to produce 4‐methoxy‐2‐nitro‐1‐phenoxybenzene ( 2 ) which further undergoes nitro reduction followed by mesylation to produce N ‐(5‐methoxy‐2‐phenoxyphenyl)methanesulfonamide ( 4 ). Furthermore, it was subjected to Vilsmeier‐Haack formylation and demethylation (using BBr 3 ) to produce N ‐(4‐formyl‐5‐hydroxy‐2‐phenoxyphenyl)methanesulfonamide ( 6 ). Subsequently, O ‐alkylation followed by NHC‐catalyzed aldehyde‐nitrile cross coupling yields the amine precursor of iguratimod ( 8 ).