Synthesis of Thiophene-Based TAK-779 Analogues by C–H Arylation

A rapid synthesis of thiophene-based TAK-779 analogues <b>1</b> is reported using a late-stage diversification strategy. At the end of the synthesis, the key building block <b>2</b>, which was prepared in six steps from thiophene, was arylated regioselectively at the α-position directly with iodoarenes. Since <b>2</b> offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system <b>2</b> into 2-aryl-substituted compounds <b>9</b>. The direct C–H arylation of <b>2</b> with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides <b>1</b> was synthesized by hydrolysis of <b>9</b> and subsequent HATU coupling with primary amines <b>4</b>.