3-Benzazocine

Total synthesis of antitumor antibiotic ER900482, 3.9-epoxy-3//-azirino[2,3-c]-l-benzazocine. 97YGK946. 

Benzannulated azocines can be prepared starting from 4-phenyl-l,2.3-benzotriazine (16), flash-vacuum pyrolysis of which leads to 2-phenylbenzazete (17) (cf. Houben-Weyl. Vol. E16c, p 939), which is stable until about 40 °C and easily enters into cycloaddition reactions with dienes. With tetraphenylcyclopentadienone, a nonisolable adduct is formed which, by loss of carbon monoxide, gives an azabicyclo[4.2.0]octatriene derivative that isomerizes to the 1 -benzazocine 18.22... 

The major adduct from C,iV-diphenyl nitrone (265) and 1 could not be isolated, as the 5-spirocyclopropaneisoxazolidine 266 underwent rearrangement under the reaction conditions, also affording the uncommon rearrangement product benzazocine 269 (Scheme 43) [66],... 

Hexahydro-3-benzazocine was reacted with EMME in boiling ethanol for 1 hr to give the 3-benzazocinylmethylenemalonate (142) in 95% yield (74USP3840522). 

The cyclization of aminoethanal acetal can be carried out in various acids. Thus, 171a-c, produced by the alkylation of the corresponding N-H derivatives with mete-methoxy-substituted benzylhalides, transform into thieno[3,2-d][2]-benzazocines 172a-c with 6N HCl (80H(14)321 Scheme 46). 

Curtius reaction of ester 196 in benzyl alcohol leads to benzylurethane 197, which by hydrolysis and catalytic reduction gives amine 198 (72JCS(P1)878, 69JCS(C)2235). The primary amino group of compound 198 was converted into dimethylamino using the Eschweiler reaction, and then selectively quaterniz. Hofmann cleavage of this salt then leads to furo[4,3,2-/g]benzazocine 199 (Scheme 54). 

Dopamine, the free catechol corresponding to (1-1), plays an important role as a neurotransmitter, particularly in the CNS. The synthesis of a dopamine-related sedative agent starts with the condensation of homoveratramine (1-1) with styrene oxide (1-2) to afford the carbinol (1-3). Treatment of that product with a strong acid leads to an attack on the electron-rich aromatic ring by the resulting carbocation there is thus obtained the benzazocine (1-4). The secondary amine is then methylated by reaction with formaldehyde and formic acid to yield trepipam (1-5) [1]. 

Of current interest are the ring expansions of (2-halophenethyl)-3//-2-benzazepines, e.g. (181), in strong base (NaH-DMSO) to dibenz[6,/]benzazecines (77CPB2875) and indolo[l,2-a][3]benzazocines (78TL1209). The reaction proceeds via intramolecular ring closure of the azepine ring onto a benzyne intermediate. 

A similar process with Diels-Alder addition of the benzazete (95) and tetraphenylcyclone followed by extrusion of CO provides a route to pentaphenyl-l-benzazocine (96) (75JCS(P1)45). 

Benz-, dibenz- and tribenz-azocinones are readily obtained by Beckmann rearrangement of the corresponding benzotropone oximes. The highly substituted 1H- 2- benzazocine (115a) is produced in an electrocyclic reaction when the ketone (115) is heated in toluene... 

Starting from the analogous TV-(2 -iodophenyl)-4-aminocyclohexanone derivative the bridged benzazocine, a framework present in several natural products, was isolated in near quantitative yield (4.7.),8... 

Dimethyl-3-(3-methyl-but-2-enyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[c/]azocin-8-ol, (2a,6a,11R )-1,2,3,4,5,6-hexahydro-6,11 -dimethyl-3-(3-mmethyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol, C19H27NO, Mr 285.42, mp 145-148 °C hydrochloride [2276-52-0], C19H27NO. ... 

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