Formyl Radical Generation from α‐Chloro N‐Methoxyphthalimides Enables Selective Aldehyde Synthesis

Abstract

The aldehydes installation by radical formylation constitutes an attractive synthetic strategy. However, the generation of formyl radicals for organic synthesis applications remains unknown. Herein we report the first formyl radical generation from α‐chloro N‐methoxyphthalimides, which selectively synthesize aldehydes by alkene hydroformylation under mild photoredox conditions. The aldehydes can be installed on acrylates, acrylamides, vinyl sulfones, vinyl ketones, and complex steroids by radical hydroformylation in excellent chemoselectivity and regioselectivity. The concerted hydrochloride elimination for the formyl radical generation from α‐chloro methoxy radicals is established by experimental and computational approaches.

Recent advances in the photocatalytic synthesis of aldehydes

“…Very recently, the group of Lan and Chen disclosed a bench-stable formylation reagent, i.e., α-chloro N-methoxyphthalimide (PhthOCH 2 Cl) 87, for the direct generation of the formyl radical under mild photoredox conditions (Scheme 20). 63 Compound 87 could be easily synthesized from the reaction of N-hydroxyphthalimide and bromochloromethane. Under the irradiation of blue light, the hydroformylation reaction of olefins including acrylates, acrylamides, vinyl sulfones, and vinyl ketones proceeds smoothly to give 4-ketoaldehydes 88 in the presence of the Ir(III) photocatalyst and Hantzsch ester (HE) as an additive.…”

Solvent-Controllable C–F Bond Activation for Masked Formylation of α-Trifluoromethyl Alkenes via Organo-Photoredox Catalysis

“…Toward this end, the radical formylation approach offers an appealing alternative to formyl metal intermediates. However, early formyl radical generation typically relied on high-energy electrolysis or irradiation, which led to a variety of parallel reaction pathways with no synthetic implementation …”

Generation and Radical–Radical Cross-Coupling of Alkenyloxy Radical

“…Generally, O radicals participate in one of four elementary reactions (Scheme b). The most common one is the hydrogen-atom transfer (HAT). , Other typical reactivities include β-fragmentation and addition to unsaturated bonds . However, cross-coupling of O radicals with other radicals is rare (limited to N–O bond formation) .…”