Rapid modular synthesis of indole ethers via dehydrogenative cross-coupling reaction of indoles and alcohols

Abstract

Indole ethers are commonly found in pharmaceuticals, enzymes, and many bioactive compounds. The cross-coupling of indoles and alcohols by activation of the indole C–H bond would provide a direct and economical way of making these medicinally active products, but this remains an elusive transformation. Here we describe a straightforward and economical protocol for the synthesis of indole ethers by indole C–H alkoxylation with cobalt catalysis. A variety of functionalized indole ethers were modularly prepared from readily accessible indoles and alcohols. The scope of the transformation was expanded to a challenging intermolecular type reaction for the one-step construction of the core scaffold of piboserod (a 5-HT4 receptor antagonist). The synthetic applications were further demonstrated by the diversification of products and synthesis of many medical agent analogues. Preliminary mechanistic investigations indicated that the salicylaldehyde-cobalt catalyst played a key role in promoting this transformation.