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A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon–carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer’s drug.

Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow

Benjamin Laroche^†, Yuki Saito^†, Haruro Ishitani^‡, and Shu̅ Kobayashi*^†‡ 

^†Department of Chemistry, School of Science, and ^‡Green & Sustainable Chemistry Social Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.9b00048

*E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00048

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