Visible-Light Photocatalytic Tri- and Difluoroalkylation Cyclizations: Access to a Series of Indole[2,1-a]isoquinoline Derivatives in Continuous Flow

Abstract

A process for achieving photocatalyzed tri-and difluoromethylation/cyclizations for constructing a series of tri-or difluoromethylated indole[2,1-a]isoquinoline derivatives is described. This protocol utilized an inexpensive organic photoredox catalyst and provided good yields. Moreover, the combination of continuous flow and photochemistry, designed to provide researchers with a unique green process, was also shown to be key to allowing the reaction to proceed (product yield of 83% in flow vs 0% in batch).

State of knowledge in photoredox-catalysed direct difluoromethylation

“…This metal-free photocatalysis in continuous flow has shown great functional group compatibility and is amenable for scale-up reactions (Scheme 29). 40…”

Visible-Light-Mediated Three-Component Cascade Sulfonylative Annulation

“… 39 Recently, a visible-light-promoted tri- and difluoroalkylation/cyclization cascade was reported by Guo and coworkers. 40 The Adiyala group has demonstrated a deaminative alkylation/cyclization continuous flow. 41 Xu and coworkers have reported a ketone-catalyzed photochemical synthesis of imidazoisoquinolinone derivatives.…”

Cascade cyclization for the synthesis of indolo[2,1-α]isoquinoline derivatives via visible-light-induced halogen-atom-transfer (XAT) and hydrogen-atom-transfer (HAT)

“…8 Several research groups have made great contributions to this research area, and have developed a series of visible-light-promoted cascade cyclization protocols for the synthesis of indolo[2,1-α]isoquinolines utilizing noble metal (such as ruthenium and iridium) complexes as photocatalysts. 9 Despite all these achievements, it should be recognized that the cost of noble metals as well as the supporting ligands raises a serious barrier in economic feasibility. Meanwhile, the issue of transition metal residue contained in organic products causes these protocols to be limited in pharmaceutical industries (<ppm level).…”