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A Convenient Synthesis of Iguratimod‐Amine Precursor via NHC‐Catalyzed Aldehyde‐Nitrile Cross Coupling Reaction
Author(s) -
Murugesh Nithya,
Karvembu Ramasamy,
Vedachalam Seenuvasan
Publication year - 2020
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202003553
Subject(s) - aldehyde , nitrile , chemistry , amine gas treating , catalysis , medicinal chemistry , demethylation , nucleophile , formylation , alkylation , coupling reaction , carbene , nitro , organic chemistry , biochemistry , gene expression , alkyl , dna methylation , gene
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 ).