Application of Heterogeneous Acid Catalysts to the Large-Scale Synthesis of 2- and 3-(p-Methoxyphenyl)-6-methoxybenzo[b]thiophenes

2-(p-Methoxyphenyl)-6-methoxybenzothiophene (3) was synthesized by acid-catalyzed cyclization and rearrangement of the β-ketosulfide precursor 1. The use of Amberlyst 15 resin as a catalyst for the cyclization increased the isomer ratio from 75:25 to 88:12, compared to a conventional approach using polyphosphoric acid (PPA). Although solid acid catalysts were also evaluated for the rearrangement, a two-phase mixture of methanesulfonic acid in toluene was found to be the best alternative to the use of PPA for this reaction. The rearrangement, which was shown to be equilibrium controlled, was driven towards completion by crystallization of the product as it formed. An Amberlyst 15 catalyzed cyclization, combined with an MsOH-catalyzed rearrangement, raised the overall isolated yield from 70 to 80%, and difficulties associated with the use of PPA on a large scale were eliminated. This process has been successfully scaled to a pilot plant and manufacturing scale.