posted on 2013-06-07, 00:00authored byAnna Junker, Junichiro Yamaguchi, Kenichiro Itami, Bernhard Wünsch
A rapid
synthesis of thiophene-based TAK-779 analogues 1 is reported
using a late-stage diversification strategy. At the
end of the synthesis, the key building block 2, which
was prepared in six steps from thiophene, was arylated regioselectively
at the α-position directly with iodoarenes. Since 2 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 2 into 2-aryl-substituted compounds 9. The direct C–H
arylation of 2 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 1 was synthesized by hydrolysis of 9 and subsequent
HATU coupling with primary amines 4.