Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon

Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from alpha-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.

Automated summary

In this study, a method for hydroxymethylation using formaldehyde as a C1 synthon is achieved through photocatalysis and a phosphine additive. By leveraging halogen-atom transfer and capturing the O-radical, the addition reaction to formaldehyde is rendered irreversible, leading to improved efficiency and yield of the reaction.