Publication details
Asymmetric organocatalyzed transfer hydroxymethylation of isoindolinones using formaldehyde surrogates
| Authors | |
|---|---|
| Year of publication | 2025 |
| Type | Appeared in Conference without Proceedings |
| MU Faculty or unit | |
| Citation | |
| Description | The cross-aldol reaction with formaldehyde is a highly efficient method for carbon chain extension, offering excellent atom economy and a significant increase in molecular complexity. Commonly used formaldehyde sources for this homologation include paraformaldehyde, trioxane, and aqueous formaldehyde. However, each of these reagents presents certain drawbacks: paraformaldehyde exhibits poor solubility in organic solvents and undergoes relatively slow depolymerization; trioxane requires acid activation; and formalin may lead to incompatibilities in catalytic systems due to the presence of water and methanol. Alternatively, anhydrous formaldehyde can be generated in situ from suitable precursors under basic conditions. These formaldehyde surrogates have not yet been systematically investigated or applied in enantioselective transformations. To evaluate their potential advantages over conventional formaldehyde sources, a challenging asymmetric hydroxymethylation of isoindolinones, originally reported by Massa et al. in 2018, was thoroughly reoptimized. By employing a piperidine-based Takemoto-type catalyst in combination with our bench-stable surrogate, we significantly improved all reaction parameters and expanded the substrate scope from 2 to 34 isoindolinone derivatives. A scale-up experiment, enantioselective downstream transformations, and preliminary mechanistic studies were also performed. |