Dearomative Photocatalytic Construction of Bridged 1,3‐Diazepanes

Abstract

The construction of diverse sp3‐rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7‐diazabicyclo[3.2.1]octanes (bridged 1,3‐diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4‐substituted quinoline substrates, with subsequent Hantzsch ester‐promoted reduction to a dihydropyridine intermediate which undergoes in situ two‐electron ring closure to form the bridged diazepane architecture. A wide scope of N‐arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all‐carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.

α-Amino Radicals via Photocatalytic Single-Electron Reduction of Imine Derivatives

“…Furthermore, this concept has been expanded to include enantioselective synthesis and utilized in iminium ion reduction for the synthesis of decorated tertiary amines and spirocycles. A substantial increase in method development in this field has been witnessed over the last five years, and the stage is set for further exploration into more challenging acceptors, generalization of enantioselective variants, and the construction of complex ring structures through radical cascades . These new directions promise to allow the photochemical single-electron reduction of imines to productive α-amino radicals to become a routine umpolung disconnection in small-molecule and natural product syntheses alike.…”

Recent advances in the dearomative functionalisation of heteroarenes

“…The Dixon group have developed an interrupted dearomative Minisci reaction of quinolines with imines ( Scheme 30 ). 36 The photocatalytic construction of bridged 1,3-diazepanes proceeds via radical addition to the C-4 position of the 4-substituted quinoline substrates 103. Subsequently, a Hantzsch ester promoted reduction gives dihydropyridine intermediates which undergo a two-electron ring closure to form the bridged diazepane core 104.…”

Uncanonical Semireduction of Quinolines and Isoquinolines via Regioselective HAT-Promoted Hydrosilylation

“…Developing mild alternative strategies capable of breaking the strong aromaticity in Lewis basic heteroaryls and with regioselective control remains an outstanding challenge. Inspired by the elegant reports of photoinduced [4+2] cycloaddition between heterocycles and olefins − or triazolinediones, − we envisaged that photo-excited-state intermediates such as 7 might be leveraged to provide regioselective hydrosilylated products 8 and reduced products 9 from abundant feedstocks in a controlled manner (Figure C). The dearomative hydrosilylation of heterocycles, in particular, might provide unique opportunities to access novel medicinally relevant scaffolds in medicinal chemistry settings.…”

“…Our dearomatization exploration commenced with the hypothesis that the photoexcited quinolinium intermediate might be reduced by a hydride reductant, − such as silane reagents, − to enable direct addition and reduction of the heteroarenes. During the solvent investigation, formation of an intriguing hydrosilylated product 11 was observed and subsequently optimized (Table , entry 1) .…”