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Published on: January 19, 2016
Asymmetric Organocatalyzed Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates
David Svestka1, Pavel Bobal1, Mario Waser2
1Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1, 612 00 Brno, Czechia.
Abstract:
The piperidine-based Takemoto catalyst has been successfully employed in a novel asymmetric transfer hydroxymethylation of activated isoindolinones, allowing us to prepare the enantioenriched hydroxymethylated adducts in good to excellent yields (48-96%) and enantiopurities (81:19-97:3 e.r.). To increase the reaction rate without compromising the selectivity, carefully optimized formaldehyde surrogates were employed, providing a convenient source of anhydrous formaldehyde with a base-triggered release. The substrate scope, including 34 entries, showed the considerable generality of the asymmetric transformation, and most entries exhibited complete conversions in 24-48 h. A scale-up experiment and multiple enantioselective downstream transformations were also carried out, suggesting the prospective synthetic utility of the products.
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