Vinyl azides in heterocyclic synthesis. Part 10. Synthesis of the isoindolobenzazepine alkaloid lennoxamine

Abstract

A total synthesis of the isoindolobenzazepine alkaloid lennoxamine (I), by a route involving vinyl azide chemistry, is described. Model studies on the azidocinnamates (12) and (13) revealed a striking difference between the (E)and (Z) -isomers; whereas the (2) -isomer (1 2) and gave largely the 1 -benzylisoquinoline (1 5) on decomposition, the (€)-isomer (13) gave the 2-aryl-3benzazepine (1 4) as the major product. Consequently, in the lennoxamine synthesis, the azidocinnamate (26) bearing the (E) -alkenyl side chain, prepared from 6-bromopiperonal via the (E) -stilbene aldehyde (25) (Scheme 4), was decomposed to give the key 2-aryl-3-benzazepine (27). Reduction of the double bonds in (27) was accompanied by cyclisation to the tetrahydroisoindolo[1,2-b] [3] benzazepine (30), which was converted into lennoxamine (1 ) by reduction of the ester group to an aldehyde, and decarbonylation.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

“…If another accessible double bond is present in the molecule, a competitive addition to this double bond can occur which can even be the main reaction. This was used by Moody and co‐workers in their total synthesis of lennoxamine ( 331 ) (Scheme ) 349…”

“…The thermal decomposition of azidoacrylates 353 in refluxing DMF produces the pharmacologically important azepino[4,5‐ b ]indoles 354 (Scheme ) 348. The synthesis of isoquinolines by insertion into sp 3 CH bonds has also been extensively investigated by Moody and co‐workers 349. In this case, the nitrene inserts into the benzhydrylic CH bond, and the isoquinoline 356 is formed after aromatization (Scheme )350.…”

Organische Azide – explodierende Vielfalt bei einer einzigartigen Substanzklasse

“…Liegt eine weitere zugängliche Doppelbindung im Molekül vor, so kann es zu einer konkurrierenden Addition an diese Doppelbindung kommen, die sogar Hauptreaktion werden kann. Diese wurde von Moody und Mitarbeitern in ihrer Totalsynthese von Lennoxamin ( 331 ) genutzt (Schema ) 349…”

“…Die thermische Zersetzung von Azidoacrylaten ( 353 ) in Dimethylformamid beim Erhitzen unter Rückfluss ergibt die pharmakologisch bedeutenden Azepino[4,5‐ b ]indole 354 (Schema ) 348. Auch die Synthese von Isochinolinen durch Insertion in C(sp 3 )‐H‐Bindungen wurde von Moody und Mitarbeitern umfassend bearbeitet;349 dabei inseriert das Nitren in die benzhydrylische C‐H‐Bindung, und es entsteht nach Aromatisierung das Isochinolin 356 (Schema ) 350. Im Falle von ortho ‐ständigen Methyl‐Gruppen oder vergleichbaren Substituenten wird ein Wasserstoffatom abstrahiert, und es bilden sich Imidochinonmethide 287.…”

Methods for the construction of [1,2]isoindolo-condensed benzazepines, benzazocines, quinolines, and isoquinolines. 1. Isoindolobenzazepines, isoindolobenzazocines. (Review)

“…By a more complicated scheme, including the cyclization of sodium 2'-[2-(benz-3-azepine)]benzoate 50a [49] to (-)-cis-11-methyl-6-oxorhoeadan 53, the chilenamine 5 is obtained with a good overall yield. When boiled in xylene the azidocinnamate 54 undergoes cyclization to 2-arylbenz-3-azepine 55, the reduction of which with sodium cyanoborohydride in acetic acid followed by nucleophilic attack by the nitrogen atom on the ester group leads to the formation of the isoindolobenzazepine 56 [51,52]. The initial azidocinnamate 54 was obtained from 2-bromopiperonal by successive transformations.…”