Publication details

Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates



Year of publication 2023
Type Appeared in Conference without Proceedings
MU Faculty or unit

Faculty of Pharmacy

Description The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for homologation reactions. However, performing this type of reaction is far from straightforward.1 Formalin solutions may cause incompatibility issues with catalytic systems due to the presence of water. On the other hand, the polymeric precursors thereof are poorly soluble in many organic solvents and have relatively low reactivity. Alternatively, anhydrous formaldehyde is generated in situ from its precursors under the alkaline conditions.2 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. A 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 24–48 h in very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,3 this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process. Additionally, several stereoretentive transformations of obtained products were accomplished.
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