Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes

Abstract

The construction of diverse sp 3 -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 1,3diazepanes) via ar eductive 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 Hantzschester-promoted reduction to ad ihydropyridine intermediate whichu ndergoes in situ twoelectron ring closure to form the bridged diazepane architecture.Awide scope of N-arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all-carbon quaternary centers.C omputational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity. Scheme 1. Photoredox catalysis in reverse polarity synthesis, and proposed concept for quinoline functionalization.

Dearomative Photocatalytic Construction of Bridged 1,3‐Diazepanes

“…The degree of π‐orbital overlap that could be achieved in the transition states of the 3 am exo and endo structures possibly has a greater effect on the energy difference than for the diastereomers of 3 aa . This change in atomic arrangement of radical addition accounts for the switch in diastereoselectivity …”

Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization

“…In addition, one-electron-based cyclizations are equally capable of dearomative structural elaborations, as was recently demonstrated with a photocatalytic reductive reaction between aldimines and quinolines that yielded bridged 1,3-diazepanes (e.g., 111 / 112). 55 Moreover, photocatalytic para-cycloaddition between pyridines and tethered olefins, proceeding through a triplet excited-state of the alkene moiety, gave unique isoquinuclidinebased polycycles (e.g., 114 / 115). 56 Dearomative cycloadditions based on the arenophile MTAD (50) were also used for expansion of arenes to oxepines (e.g., 116 / 117).…”

Automation of Synthesis in Medicinal Chemistry: Progress and Challenges

“…Preprepared kits of photocatalysts, bases, and solvents have been designed to allow use by the nonexpert. Photochemistry is now being used more widely to enable the production of novel and complex chemotypes as exemplified by a recent paper showing the screening of a wide range of photocatalysts, bases, and solvents to find conditions for the synthesis of bridged 1,3-diazepanes (Scheme ). Lowering these barriers will certainly be beneficial for chemists wishing to access alternative chemistry space.…”