Polycyclic Indoline‐Benzodiazepines through Electrophilic Additions of α‐Imino Carbenes to Tröger Bases

Abstract

Polycyclic indoline‐benzodiazepines can be accessed through the intermolecular reaction of Tröger bases with N‐sulfonyl‐1,2,3‐triazoles. Under RhII catalysis, α‐imino carbenes are generated and a subsequent cascade of [1,2]‐Stevens, Friedel–Crafts, Grob, and aminal formation reactions yield the polycyclic heterocycles as single isomers (d.r.>49:1, four stereocenters including two bridgehead N atoms). Further ring expansion by insertion of a second α‐imino carbene leads to elaborated polycyclic 9‐membered‐ring triazonanes.

Configurational Lability of Imino‐Substituted Ethano Tröger Bases. Insight on the Racemization Mechanism

“…As mentioned, [43] compounds of type 4 present a unique combination of benzodiazepine and indoline scaffolds that are major pharmacophores. [44,45] For potential medicinal chemistry or agrochemical applications, the isolation of derivatives 4 in single enantiomeric forms was considered a necessity.…”

“…The reaction proceeded well, with the same reported yield of 70 % as with rac-1. [43] However and quite disappointingly, 4a was isolated in racemic form. Several triazole reagents with various combinations of substituents were tested (R 2 = p-MeO-C 6 H 4 , COOMe; R 3 = p-NO 2 -C 6 H 4 , Me).…”

“…More specifically, care was taken to evaluate the mechanism and pinpoint the elementary step(s) responsible for the deleterious effect. At the start of the study, the mechanistic rationale was the following (Scheme 5): [43] First, Nsulfonyl triazoles react and generate α-imino carbenes A' by nitrogen extrusion in the presence of Rh 2 (Piv) 4 . Then, upon reaction with TB 1, ylides B' are formed.…”

“…[36] Recently, TB 1 was treated with aryl α-imino carbenes; these intermediates are generated from the corresponding N-sulfonyl-1,2,3-triazoles [37 -42] under Rh (II)-catalysis at 80°C. [43] Original polycyclic indolinebenzodiazepines 4 resulted from the transformation through a cascade of [1,2]-Stevens rearrangement, Friedel-Crafts, Grob fragmentation, and aminal formation reactions (Scheme 3). [43] As the nature of the reagents and intermediates is comparable in both transformations 1!3 and 1!4, a high enantiospecificity was expected for the latter reaction.…”

Nucleophilic‐Addition‐Initiated Ring Expansion and Selectivity in Anionic Fragmentation

“…In this article, we will present the developments that gather together the concepts of anionic fragmentations and selectivitya ppliedt ot he ring expansion tactic of unstrained cycles. [3][4][5][6] In the field, Rodriguez and co-worker reported in 1997 the MARDi cascadet hat stands for Michael Aldol retro-Dieckmann (Scheme 2). [7] Starting from cyclic b-ketoester 1,t he authors condensed the pronucleophile with ad ual electrophile such as acrolein in the presenceo fabase.…”