Fused Azepines

The Beckmann and Schmidt reactions are applicable to the synthesis of azepines fused to other heterocyclic and carbocyclic systems, such as pyridoazepinones (70JA203, 76AP550, 78JHC249), indoloazepinones (78CB1780) and the 14v aromatic azabenzazulen-nones (204) (80BCJ3232). The general chemistry of azaazulenes has been reviewed <81H(15)547>. 

Dieckmann cyclizations of diesters of type (210) are catalyzed by potassium f-butoxide in toluene, sodium in xylene, or sodium hydride in DMF, and produce 1-benzazepinones in good yields. The method is also applicable to the synthesis of azepines fused to other heterocycles, e.g. pyrrolo[2,3-6]azepin-4-ones (211) (81H(16)399). 

Azepines, fused, from thermolysis of perfluoroanilines with acetophenone,... 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

The alicyclic analogs 4 with hydrogen bromide in diethyl ether at room temperature behave similarly to yield the 4,5-fused 7-bromo-3/7-azepin-2-amines 5 as their hydrobromide salts. Yields are high except for the cyclooctane derivative (n = 4). Once again, the free bases are liberated by treatment with sodium hydrogen carbonate. 

Likewise, the isomeric fused aziridines 22 and 24, obtained from 1,4,5,6,7,8-hexahydronaph-thalene, undergo bromination. dehydrobromination and ring expansion to the 6,7,8,9-tetra-hydro-3//-3-benzazepine 23 and the 2,7-bridged azepine 25, respectively.61... 

Ring contraction to 3 6 fused, e.g. 17, rather than 4 5 fused ring systems, accompanied by phenylation, occurs on treating l//-azepine-l-carboxylates, e.g. 16. with pailadium(II) acetate in benzene solution.242 In solvents other than benzene, ring-scission products result (see Section... 

In a series of three papers, Noguchi and co-workers have reported their continuing studies on the formation of heterocycle-fused azepine systems <96X13081, 96X13097, 96X13111>. A typical example is the conversion of the aldehyde 15 into the azepines 16 and 17 (Scheme 3). Xhe reaction also proceeds with imines when the dihydroazepine prior to bridging can be isolated. Mechanistic and stereochemical aspects of the reaction have been explored. 

Indolones and isoindolones have been utilised in the synthesis of fused azepine derivatives. In the one reaction, rearrangement of the alkynes 18 to 2-benzazepine-l,5-diones 19 in the presence of Lewis acids has been reported <96XL393>. Xhe yields vary from moderate to very good. Xricyclic azepines 20 are obtained by the reaction of the 4-[2 -(p-toluenesulfonyloxy)ethyl]-2-oxindole with imines <96JHC209>. 

Reduced fused azepines (e.g. 40) have been used in a new ring expansion strategy to afford fused hexahydroazoninoindoles (e.g. 41) from reaction with methyl propiolate in methanol to give the ylide intermediate A which then ring expanded via the methanol stabilised intermediate B to give 41 <06T1239>. 

Similarly, [4 + 2]-cycloadditions were used to prepare the pyridazine moiety in fused tetraheterocyclic azepine 155 syntheses. In this reaction, the 1,2,4,5-tetrazines 154 function both as the 47t-components and the oxidizing agents thereby requiring four equivalents of tetrazine for optimal yield. . 

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then iV-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>. 

The synthesis of the previously undescribed 4,6,7,8-tetrahydropyrrolo[2,3-d]azepine ring system has been reported, based on pyrroles or azepinedione derivatives. For example, reaction of the azepinedione shown below with benzylamine in the presence of p-toluenesulfonic acid gave the fused derivative 26 <0OM104>. 

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused l-azabicyclo[m.n.O]alkanes, the perhydrobenzo[/]pyrrolo[l,2-a] azepine 29 was prepared in 72% yield . 

A library of piperazine containing fused azepine-tetrazoles 183 was built by Nixey et al. via Ugi reaction in the solution phase [55]. This library comprises an example of a building block introduced piperazine (Scheme 32). The reaction of A-Boc-a-amino aldehyde 184, methyl isocyanoacetate 185, substituted piperazines 186, and trimethylsilylazide 181 in methanol, followed by acid treatment, proton scavenging, and reflux affords bicyciic azepine-tetrazoles 183. This efficient protocol with three diversity points can be used to generate arrays of biologically... 

Scheme 32 Synthesis of piperazine incorporating fused azepine-tetrazoles 183 and two representative 3D conformations of 183A blue) and 183B cyan)...

Nixey T, Kelly M, Semin D, Huhne C (2002) Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Lett 43(20) 3681-3684... 

Some related cyclic scaffolds, such as the azepines, were obtained by Ugi-4CR/ RCM combinations (Fig. 5a) [61], and fused benzodiazepine/triazole frameworks were derived from sequential Ugi-4CR/alkyne-azide dipolar cycloaddition (Fig. 5b) [62]. Both are considered as interesting (3-tum mimics. Similarly, bicyclic systems featuring fused DKP rings (Fig. 5c) have been reported to mimic the ten-membered pseudo-cycle of type 1 (3-tums [63, 64]. 

The special case of the fusion of a five-membered ring to the benzoheteropine ring occurs when the pyrrole or indole N1 and C2 atoms serve as fusion sites (Figure 2). The resultant benzopyrrolo[l,2-fl]azepines differ by the position of the fused benzo ring and are listed in the order of benzo[c]pyrrolo[l,2-fl]- (7), benzo[d]pyrrolo[l,2-fl]- (8), benzo[e]pyrrolo[l,2-fl]- (9) and benzo[/]pyrrolo[l,2-fl]-(10) azepines, respectively. 

Intramolecular electrophilic reactions of substituted pyrrole-2-carboxylic acids or their amides lead to benzo[d]pyrrolo[l,2-a]azepinones. Acid 70 in this fashion undergoes Fiiedel-Crafts cyclization to furnish fused azepine 71 in good yield (Equation (6) (2000JOC2479)). 

An example of electrophilic substitution on position C2 of the fused furan has been reported for 8H-furo[3,4-d]dibenz[ 7,/]azepine, which reacts with f-butyl hypochlorite to afford a mono chlorinated furan ring product (1995H431). 

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