Development of a solid-compatible continuous flow reactor for the paraformaldehyde slurry mediated α-hydroxymethylation of methyl vinyl ketone†

The α-hydroxymethylation reactions hold a significant position within the pharmaceutical industry due to their intriguing nature. Despite numerous reported methods, they often entail prolonged reaction times and moderate yields. Moreover, the prevalent use of aqueous formaldehyde restricts the applicability of this chemistry to water-compatible substrates. Gaseous formaldehyde remains largely avoided due to its toxicity, hazards, and requirement for substantial excess. Within this context, paraformaldehyde emerges as a promising alternative for the C1 building block, offering safety and ease of handling. Continuous flow methodology is employed to facilitate the in situ depolymerization of paraformaldehyde under optimized conditions, enabling direct utilization of the released formaldehyde gas. This research explores the use of a paraformaldehyde slurry in continuous flow for α-hydroxymethylation reactions, with methyl vinyl ketone serving as a proof-of-concept substrate. A solid-compatible continuous flow reactor was self-constructed and the hydroxymethylation of methyl vinyl ketone could successfully be optimised, resulting in a STY of 2040 kg h⁻¹ m⁻³.