An Efficient Process for the Large-Scale Synthesis of a 2,3,6-Trisubstituted Indole

The efficient synthesis of a key trisubstituted indole intermediate 1 is described. The synthetic route required the use of an aryl Grignard reagent which was not commercially available, and the large-scale formation of this fragment and the thermal evaluation for this step is presented. The key step in the sequence was a Truce–Smiles rearrangement to provide an advanced ketone intermediate which, upon reduction, cyclized to the desired indole 1. Design of experiment (DoE) optimization of this reduction is also presented. In total >50 kg of target indole 1 were synthesized in 55% overall yield over five steps using this new route.