Fused azepine

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>. 

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 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... 

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)). 

Diisobutylaluminium hydride may even be used to promote the rearrangement in O-unsubstituted oximes. Several heterocyclic fused azepines 475 were synthesized from the corresponding cyclohexanone oximes (equation 203). 

Formation of l-aryl-l//-azepines is rare and occurs only with those arylnitrenes made sufficiently electrophilic by an electron-withdrawing, e.g. CN, N02 or CF3, ortho or para substituent. Even so, these docile nitrenes attack only electron-enriched arenes (e.g. mesity-lene or Af,Af-dimethylaniline) and are of minor synthetic importance (B-73MI51600). More reactive are 7r-deficient heteroarylnitrenes, and moderate yields (15-40%) of 1-heteroaryl-l//-azepines, e.g. (228 R=4,6-dimethoxy-l,3,5-triazin-2-yl), may be obtained by the photodecomposition of 2-azido-4,6-dimethoxy-l,3,5-triazine in a variety of aromatic substrates (81BCJ301). Interestingly, intramolecular insertion of arylnitrenes into arenes is more common and has been used for the synthesis of fused azepines, e.g. the azepinoindoles (229) from o-azidodiphenylmethanes (81JCS(P1)1132). 

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). 

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>. 

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). 

Workers at Amgen further exploited this reaction in an attempt to access 6,5-fused ketopiperazine-tetrazoles 96 and 7,5-fused azepine-tetrazoles 94, respectively (Scheme 12). Thus, reaction of methyl-isocyanoacetates 92,... 

Electrochemical reduction of the pyridinium compounds (22, R = H, Bu1), prepared by reaction of 6-bromohexan-2-one and the respective pyridine, yields mixtures of the the fused azepines (23) and (24), albeit in low yield <95aG(K)2007>. A new synthesis of claviciptic acid has been published <95Joci486>. 

An alternative approach to functionalised azepine derivatives has been reported by Occhiato et al. [02JOC7144] involving a Pd-catalysed cross coupling reaction of the vinyl triflate 33 with the oi-alkoxyboronate 3 4 (R = H) to give 35 in 45% yield acid catalysed hydrolysis then afforded the azepine derivative 37 and the fused azepine 36 in low to fair yields respectively. 

Ring construction approaches have also been used effectively in the diastereoselective synthesis of the fused azepine 43 from the pyrrolidinone 41 and (Z)-l,4-dichloro-2-butene 42 [01TA2205], and in the synthesis of the alkaloid 275A (44) from the Colombian poison frog Dendrobates lehmanni [01JNP421]. 

A variety of other ring fused azepines and azepinones have been described. Kocevar et al. have reported the first syntheses of the pyrano azepinediones 70 and 71 from 69 via the Schmidt reaction at -15 °C to 0 °C (in CHCh or CH2CI2) the products 70 are favoured, while at 32 °C to 35 °C the percentage of the isomers 71 increased overall yields were high... 

Other fused azepines, with aromatic (e.g. 94a,b) or heteroaromatic fused rings (e.g. 94c,d) have been prepared via the Af-acyliminium ion intermediate 93 in high yields lactam reduction then yielded the respective amines 95a,b and 95c,d [01H1519]. An intramolecular Friedel-Crafts reaction has been used to synthesise the fused azepinone 99 (S,S configuration) from 98, the latter being prepared from the diastereopure a-hydroxylactam 96, via the acid 97 [02H449],... 

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. 

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>. 

The oxirane fused azepine 40, formed by an intramolecular [5+2] cycloaddition reaction undergoes an acid promoted rearrangement to yield the tricyclic derivative 41. The structure was confirmed by X-ray crystallography of the nitrobenzoate ester <07OL4681>. 

The heterocyclic hemi-aminal 44 was formed as a model for the synthesis of the marine alkaloids zoanthamine and zoanthenol and is derived from the cyclic imine formed by the reduction of an appropriated substituted azide <07H(72)213>. A pyrrolidine-fused azepine has been isolated from the venom of the ant Myrmicaria melanogaster and assigned as 45 based upon GC and FT-IR comparison with synthetic material <07JNP160>. The axially chiral doubly bridged biphenyl azepine 46 has been synthesised and used with oxone as an epoxidation catalyst in a biphasic system <070BC501>. 

A new Stemona alkaloid sessilifoliamide C, 41 (from Stemona sessilifolia) has been described with a fused azepine skeleton a butanolide analogue (sessilifoliamide B) was also isolated <03T7779>. 

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>. 

Addition of a 2-methylquinazolin-4-one to DMAD over a long time at the boiling point of acetonitrile leads to the formation of a new fused azepine ring. A two- or three-fold excess of methyl propioiate reacts with 2-methylbenzothi-azole in a similar fashion. 

A(-Phenyl-2-vinylaziridines and their heterocyclic analogues, e.g. (16), are known to rearrange to give benzo- or hetero-fused azepines, e.g. (18). A, 1... 

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