Preparative [3+2] cycloaddition of CH2N2 to acrylate derivatives: revising, scope and synthetic applications

Safe and preparative approaches using flow chemistry technologies were applied to the known [3+2] cycloaddition of diazomethane with a diverse set of substituted methyl acrylates. The initially formed Δ¹-pyrazolines were also subjected to in-flow transformations. DFT modelling of the [3+2] cycloaddition predicts a concerted asynchronous mechanism for the reaction. The observed in the experiment regio- and stereoselectivity of the transformation are kinetically driven. Some of the initially formed Δ1-pyrazolines tend to isomerize spontaneously to Δ2-isomers. However, conditions suitable for isolating Δ¹-pyrazolines, previously considered unstable, have been discovered. Other [3+2] cycloaddition products were found to be stable on isolation and storage. By treatment of the formed Δ1-pyrazolines with strong acid (HCl), hydrochlorides of isomeric Δ2-pyrazolines have been isolated. Photo-induced nitrogen elimination from Δ1-pyrazolines in the flow photo reactor provides an easy approach for the preparative synthesis of a broad series of cyclopropanes, which are valuable motifs in pharmaceuticals and agrochemicals. The reaction proceeds under mild conditions with preservation of configuration of stereocenters. All the reactions are easily scalable at least up to several tens of grams. This work demonstrates that a deep mechanistic understanding of the reaction pathways, combined with the advantages of flow chemistry and photochemical techniques, can transform a classic reaction into a practical and scalable synthetic methodology.