Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates
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| Year of publication | 2023 |
| Type | Appeared in Conference without Proceedings |
| MU Faculty or unit | |
| Citation | |
| Description | The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. However, performing this type of reaction is far from straightforward. Formalin solutions may cause incompatibility issues with many catalytic systems due to the water presence. On the other hand, the polymeric precursors thereof (para- or metaformaldehyde) are poorly soluble in many organic solvents causing the slow release of the reactive monomer and overall reaction slowdown. For these reasons, research on bench-stable, soluble, and reactive formaldehyde surrogates (“H2C=O cans”) for catalytic reactions is highly desired. Since the formaldehyde releasers have never been systematically investigated, we synthesized and evaluated more than 20 formaldehyde surrogates in a model asymmetric methylolation of isoindolinones. Thorough screening of our catalyst library revealed that the bifunctional molecules containing basic moieties (i.e., Takemoto-type catalysts) provided the best enantioselective outcomes. Next, a series of optimizations was performed to establish the most suitable reaction conditions. A combination of the above catalysts with the triazole-based formaldehyde surrogates furnished the hydroxymethylated products within 24 h in the very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process. |
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