High-throughput C-H Activation in a Bead-Beater Homogenizer: Fast and Regioselective Access to 2-Arylindoles

Abstract

There are not many attempts at high-throughput mechanochemical synthesis. A bead-beater homogenizer with 24-64 slots offers a unique opportunity for high-throughput mechanosynthesis (HTMS). In this study, C-H bond activation is achieved by homogenizing multiple samples at-one go in simple polypropylene (PP) vials with stainless steel balls via liquid-assisted grinding (LAG); they still employ enough frictional force to achieve this challenging transformation. The method demonstrates the preparation of synthetically useful 2-arylindoles through a regioselective reaction between N-alkylated indoles and aryl iodides, catalyzed by Pd(II) and facilitated by C2-H activation in the absence of phosphine ligands, using a bead-beater homogenizer. 5 mol% of Pd(OAc)2 was sufficient to catalyze C2-activation of indoles in the presence of a small volume of EtOAc as the LAG agents, affording 2-arylindoles in high to excellent yields, mostly in 9 min. The method demonstrated excellent tolerance to structural variations, including electron-rich and electron-deficient substituents, in both indoles and iodoarenes. However, unprotected indoles or indoles with deactivated five-membered rings could not participate well in the reaction. The simple, high-yielding, ambient-temperature high-throughput mechanochemical protocol is devoid of a formal workup step, and with a low E-factor (4.5) and a high Eco-scale score (78.5), it augments well with sustainability matrices.