Fused azepines and derivatives

Ring closing metathesis has been applied successfully to the preparation of the fused azepine 40 (accessed in moderate yield from 37 via 38 and 39), which was then converted via 41 to the fused sugar analogue 42 05TL2295 . 

An asymmetric route to the fused azepine derivatives 44 has been reported by Pedrosa et al. 05EJO2449 . The power of ruthenium-catalysed ring closing metathesis is further demonstrated in this synthesis, involving conversion of 43 to 44 (e.g. with R = H, R = CH3 82% yield, 92% de). Compounds of type 44 could then be readily converted into the reduced azepin-3-ol derivatives 47 via 45 and 46. 

The Pd-eatalysed reaction of 48 with allyltributyltin to give 49, followed by Af-alkylation to 50, then gave the 1-benzazepine derivative 51 in high yield on Ru-catalysed ring closing metathesis 05JOC1545 . 

The solid- and solution-state structures of the 7-membered ring in 1-benzazepine-derivatives has been reported 05JOC1545 . 

The potent electrophilicity of the Af-acylirniniurn ion intermediate 54 (generated from 52 via 53) was used effectively to access the 2-benzazepin-3-ones 55 (e.g. R = H, = Ph, 31%) in fair to good yields 05SL2791 . The A -substituted analogues 59 (e.g. R = H, R = Ph, R = Bn) could be prepared via the same type of reactive intermediate 58 but generated in this latter case by SbCls-mediated addition of the acid chlorides 56 to the imines 59 05SL2791 . 

The fused azepine 29 was formed unexpectedly by the cyclisation of the Al-arylsulfonyl caprolactam 28 as a competing reaction for the formation of the alkcnylphosphonite 30 07OBC3472 . The cyclisation was also specific for the seven-membered derivatives, with pyrrolidinone and piperidinone derivatives yielding the phosphonites as the only products. The mechanism is believed to be initial ortho-lithiation followed by nucleophilic addition to the lactam followed by dehydration. 

Bicyclic azepine 33 was formed by the conjugate addition of a piperidine to a tethered a,P-unsaturated ester 32 which was formed by the Morita-Baylis-Hillman reaction of the corresponding aldehyde 31 07JOC5608 . 

Reagents (i) CH2=CHC02CH3, DABCO (ii) AcCI, pyridine CH2CI2 (iii) CF3C02H, CH2CI2, 0 °C 

The Schmidt reaction was used for the ring expansion of the ketone 34 to yield the dihydropyrido fused caprolactams 35 that showed hypotensive activity 07MC219 . 

A small library of isoxazole fused azepines 39 was synthesised by the acid catalysed conjugate addition of 3,5-dimethyl-4-nitroisoxoazole 36 to a,p-unsaturated ketones 37 yielding the adduct 38 followed by tin(II) chloride reduction of the nitro group and imine formation 07ARK266 . 

A palladium-catalysed intramolecular hydroamidation (using 39 as the catalyst) with the amido alkyne 37 proceeded regioselectively in the presence of base (KOH or NaOEt) to provide access to the 3-benzazepin-2-one 38. This reaction can also accommodate other alkynes 06TL3811 . 

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 . 

The imidazo-benzazepine 43 was prepared in moderate yield by a combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a microwave-promoted intramolecular Heck reaction 06TL3225 . 

An intramolecular nitrone 1,3-dipolar cycloaddition reaction to give 46 from 45 followed by reductive N-O bond cleavage afforded a stereoselective synthesis of the tetrahydro 177-1-benzazepines 47 the nitrone precursors 44 were prepared in turn by a Claisen rearrangement from an IV-allylamine 06SL2275 . 

Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to provide access to the amino ester 48 which could then be converted, via 49 and 50, into the chiral substituted 1-benzazepine derivative 51 06OL2667 . 

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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>. 

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>. 

This review is based on Mosby s book cited above and covers the literature through 2009 together with several articles published in 2010. It includes pyrido[l,2-fl]azepines and their hydro products as well as linearly or angularly fused benzo and dibenzo derivatives. Patents are taken into account provided they reveal important aspects of synthesis or application. 

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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