Publication details
Asymmetric Organocatalytic Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates
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| Year of publication | 2024 |
| Type | Appeared in Conference without Proceedings |
| MU Faculty or unit | |
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| Description | The cross-aldol reaction with formaldehyde is a highly efficient method for extending carbon chains that is greatly rewarding in terms of atom economy and increased molecular complexity. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for this homologation reaction. Nevertheless, their use has several disadvantages – paraformaldehyde is poorly soluble in organic solvents and has relatively slow chain unzipping, trioxane requires activation with acid, and formalin may cause incompatibilities in catalytic systems owing to the water and methanol presence. Alternatively, anhydrous formaldehyde can be generated in situ from its precursors under the basic conditions. These formaldehyde surrogates have never been systematically investigated and used in enantioselective reactions. To test their superiority over other formaldehyde sources, a challenging asymmetric hydroxymethylation of isoindolinones, which was first reported by Massa et al. in 2018, was utterly reoptimized. By employing a combination of the piperidine-based Takemoto-type catalyst and our bench-stable surrogate, we were able to dramatically improve all reaction parameters and expand its scope from 2 to 34 isoindolinone derivatives. A scale-up experiment, enantioselective downstream transformations and preliminary mechanistic elucidations were also carried out. |
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