Fused azepine derivatives

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>. 

This method has been utilized to construct other fused azepine derivatives, e.g., 85 from indolylallenes 83 (Scheme 26). Indirect evidence for the involvement of the azomethine ylides 84 came from their trapping in a [3 + 2] cycloaddition (97JOC7744). 

An asymmetric route to the fused azepine derivatives 192 has been reported by Pedrosa et al. <2005EJO2449> involving conversion of 191 to 192 (e.g., with R1 = Ph, R2 = H, R4 = H 90% yield) (Scheme 25). Compounds of type 192 could then be readily converted to the reduced azepin-3-ol derivatives 193 (Scheme 25). 

In an intriguing dearomatizing transformation, the thiophenecarboxamide 91 underwent conversion to the fused azepine derivatives 92 upon treatment with LDA, followed by introduction of electrophiles. The mechanistic aspects of this, and some related reactions were also discussed <04CC2430>. 

The Diels-Alder reaction of benzynes offers a route to the synthesis of fused azepine derivatives. Thus it is possible to convert the furan (15) into the fused system (16) in approximately 50% yield by reaction with LiTMP in THF at -78 °C... 

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>. 

A different approach to azepine derivatives involved a Pd-catalyzed cross-coupling reaction of the vinyl triflate 49 with the a-alkoxyboronate 50 (R = H) to give 51 in 45% yield acid-catalyzed hydrolysis then gave the azepine derivative 52 and the fused azepine 53, although yields were modest (Scheme 5) <2002JOC7144>. 

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