Syntheses of Aporphine and Homoaporphine Alkaloids by Intramolecular ortho-Arylation of Phenols with Aryl Halides via S_RN1 Reactions in Liquid Ammonia

Abstract

The photostimulated intramolecular ortho-arylation reactions of bromoarenes linked with pendant phenoxy containing N-substituted tetrahydroisoquinolines in liquid ammonia afforded aporphine (54-82% yield) alkaloid derivatives via SRN1 reactions. This strategy was extended for the first time to the synthesis of a homoaporphine derivative (40% yield). Tetrahydroisoquinoline precursors that contained electron-withdrawing groups on nitrogen (i.e., amides, sulfonamides, and carbamates) gave cyclized products, whereas precursors with basic nitrogens (i.e., NH or NMe) either failed to yield cyclized products or gave aporphines in only low yield.

Iterative double cyclization reaction by SRN1 mechanism. A theoretical interpretation of the regiochemical outcome of diazaheterocycles

“…15 An S RN 1 synthetic strategy to obtain heterocyclic compounds was previously developed based on the intramolecular cyclization of substrates bearing both the leaving group and the nucleophilic center. 16 This methodology has been recently applied to the synthesis of 1-phenyl-1oxazolinoindan derivatives and their related compounds; 17 tetracyclic isoquinoline derivatives; 18 a series of substituted 9Hcarbazoles and carbolines; [19][20][21] aporphine and homoaporphine alkaloids; 22 pyrroles, indoles, and pyrazoles; 23 indazoles; 24 pyridio[1,2-a]benzimidazoles; 25 2-pyrrolyl and 2-indolyl benzoxazoles, 26,27 among others. Moreover, an intermolecular S RN 1 reaction of substituted iodobenzylamines with several tetralones afforded a series of benzo[c]phenanthridines with modest overall yields after several steps.…”

Modern Developments in Aryl Radical Chemistry

“…A comparable cyclization under S RN 1 conditions [123,124] has been reported by Cuni and Rossi [125]. Alternatively, electrochemical generation of aryl radicals can be employed [126].…”

Intra- versus intermolecular electron transfer in radical nucleophilic aromatic substitution of dihalo(hetero)arenes – a tool for estimating π-conjugation in aromatic systems

“…1 This process has been applied to the synthesis of natural products 2 and also in neighboring disciplines for the preparation of oligomers 3 and polymers. 4 Its radical chain mechanism was first proposed by Kornblum 5 and Russell 6 for activated aliphatic and aromatic substrates.…”