Pd‐catalyzed direct acylation reaction of iodoacetanilides/iodophenyl acetates with aldehydes is presented. Simple, bench‐top aldehydes were used as non‐toxic acylating agents. This protocol comprises direct coupling with aldehydes without activating the carbonyl group and without directing group assistance. The strategy was applied to a domino one‐pot synthesis of 2‐quinolinones through acylation and intramolecular aldol condensation. Significantly, the strategy was extended to the domino one‐pot synthesis of drugs and bioactive compounds.

The Front Cover shows a domino directing group free one‐pot synthesis of 2‐quinolinones from ortho‐iodoacetanilides by palladium catalyzed direct acylation as the key step. The background represents a water source, signifying that the reaction is water tolerant and water in the TBHP helped to promote the reaction. Non‐toxic aldehydes are used as acylating agents instead of toxic CO gas. In addition, one‐pot formation of ortho‐acylanilines via in situ base hydrolysis of ortho‐iodoacetanilides is also presented. Significantly, the strategy was extended to the domino one‐pot synthesis of drugs and bioactive compounds, for example, the syntheses of an HBV inhibitor and a key intermediate of Tipifarnib. More information can be found in the https://doi.org/10.1002/ejoc.201701250.