Chemoselective Strategy for the Direct Formation of Tetrahydro-2,5-methanobenzo[c]azepines or Azetotetrahydroisoquinolines via Regio- and Stereoselective Reactions

Abstract

The present study reports regio- and highly diastereoselective preparative methods for the synthesis of versatile alkaloid-type compounds from oxiranylmethyl tetrahydroisoquinolines. 2,5-Methanobenzo­[c]­azepines or azetidine-fused heterocycles were synthesized in tandem reactions depending on the absence or presence of a BF3 co-reagent. A high functional group tolerance has also been demonstrated. DFT calculations with an explicit solvent model confirmed the proposed reaction mechanisms and the role of kinetic controls on the stereochemical outcome of the reported new methods.

Regio- and Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin’s Rules for the Ring-Formation Reactions of Oxiranes

“…However, it should be emphasized that the reactions of the very similar tetrahydroisoquinoline derivatives have different routes, yielding completely different bridged heterocyclic systems. 63 …”

“…The N -oxiranylmethyl isoindole did not afford the desired fused heterocyclic product under the conditions applied. However, it should be emphasized that the reactions of the very similar tetrahydroisoquinoline derivatives have different routes, yielding completely different bridged heterocyclic systems …”

Transition‐Metal‐Free Methods for the Remote C−H Bond Functionalization of Cyclic Amines

“…In 2019, Kovács and co‐workers reported the formation of tetrahydro‐2,5‐methanobenzo[ c ]azepines such as compound 57 via β ‐lithiation of THIQs followed by nucleophilic addition of the generated carbanion to the N ‐tethered epoxyethane moiety (Scheme 23). [53] Potassium t ‐butoxide/LDA super base is used for the deprotonation. It is worth to mention that a divergent reaction occurs when the substrate is deprotonated with lithium 2,2,6,6‐tetramethylpiperidide (LiTMP) in the presence of BF 3 ⋅OEt 2 , where the α ‐amino carbanion is formed and attacks the epoxyethane to afford azetotetrahydroisoquinoline product.…”

C(sp3)–H cyclizations of 2-(2-vinyl)phenoxy-tert-anilines

“…Therefore, nding novel approaches for their preparation could be also of signicant practical value. 44,45 The aim of the present work was to study in more detail the synthetic scope of the cyclization of biaryl ethers (14 / 15), potentially furnishing oxazonine derivatives via hydride transfer from an N-alkyl group to an electron-decient alkene, facilitated in principle by the proximity of the groups and the electron-rich character of the N-alkyl group. 46 To explore the frontiers of the cyclization, the respective CH 2 -analogues were tested as well (16 / 17 and 18 / 19).…”

“…Therefore, finding novel approaches for their preparation could be also of significant practical value. 44,45…”