Continuous‐flow Synthesis of Aryl Aldehydes by Pd‐catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen

A continuous‐flow protocol utilizing syngas (CO and H(2)) was developed for the palladium‐catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process‐intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO‐to‐H(2) stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H(2)=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good‐to‐excellent yields (17 examples). In particular, a successful scale‐up was achieved over 415 min operation time for the reductive carbonylation of 2‐bromo‐6‐methoxynaphthalene to synthesize 3.8 g of 6‐methoxy‐2‐naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.