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

ABSTRACT: A continuous-flow protocol utilizing syngas (CO and H₂ ) 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-H₂ 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/H₂ =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.

SUBMITTER: Hone CA 

PROVIDER: S-EPMC6582436 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature