Diverse methyl sulfone-containing benzo[b]thiophene library via iodocyclization and palladium-catalyzed coupling

Abstract

Parallel solution-phase methods for the synthesis of a 72-membered benzo[b]thiophene library are reported. Medicinally interesting, drug-like, methyl sulfone-substituted benzo[b]thiophenes have been prepared by the palladium-catalyzed substitution of 3-iodobenzo[b]thiophenes by Suzuki-Miyaura, Sonogashira, Heck, carboalkoxylation, and aminocarbonylation chemistry. The key intermediates for library generation, methyl sulfone-containing 3-iodobenzo[b]thiophenes, are readily prepared by iodocyclization and oxidation methodologies from readily available alkynes.

Figure 1

Chemical structures of known selective COX-2 inhibitors and synthetic benzothiophene SERMs, such as CH₃SO₂-DMA (III)

Figure 2

Sublibraries of boronic acids 7, terminal alkynes 8, styrenes 9, alcohols 10, and amines 11

Scheme 1

Parallel Synthesis of Multi-substituted Benzo[b]thiophenes

Scheme 2

Library Design for a Diverse Methyl Sulfone-substituted Benzo[b]thiophene Library (6)