Synthesis of Benzo-Fused 1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction:  A Formal Synthesis of Gephyrotoxin

Abstract

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

Synthesis and Some Biological Properties of Pyrrolo[1,2‐a]indoles

“…An intramolecular Schmidt reaction with formation of 2,3‐dihydropyrrolo[1,2‐ a ]indole 282 was studied . It was demonstrated that the interaction between azide 283 and trifluoromethylsulfonic acid proceeds via formation of intermediate aminodiazonium ion 284 and 1,2 CN rearrangement followed by the elimination of N 2 leading to the indolinium salts.…”

Enantioselective Synthesis of 2,3‐Dihydro‐1H‐benzo[b]azepines: Iridium‐Catalyzed Tandem Allylic Vinylation/Amination Reaction

“…An X-ray crystallographic analysis of enantiopure 3 m disclosed the absolute configuration as R. [14] Notably, as evidence for the proposed reaction pathway (Scheme 1), the intermediate 4 could be isolated. An X-ray crystallographic analysis of enantiopure 3 m disclosed the absolute configuration as R. [14] Notably, as evidence for the proposed reaction pathway (Scheme 1), the intermediate 4 could be isolated.…”

Six‐Membered Heterocycles: Quinoline and Isoquinoline

“…In this way, gephyrotoxin, a naturally occurring substance isolated from the secretions of the poison-dart frog Dendrobates histrionicus, was prepared [157]. 17.1.5 General Reactivity: Useful Reactions 17.1.5.1 Addition to Nitrogen As in pyridine, the nitrogen in quinoline undergoes protonation, alkylation, acylation, N-amination [158], and with peroxyacids or in the presence of other oxidative systems, such as O 2 /2-methylpropanal [159], oxidation to the N-oxide.…”