Azepine ring system

Few examples are reported for triazino[x,y-z]azepine ring systems. 

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>. 

Mirtazapine 105, a polycyclic pyridine derivative containing a pyridine ring fused with an azepine ring system, is an antidepressant <2006W02006/008302>. The piperidine derivatives paroxetine 106, alnespirone 107, and Azaloxan... 

The general family of pyrimidoazepines encompasses seven distinct heterocyclic systems (1-7, see Fig. 1). Of these, only compounds containing the pyrimido[5,4-c]azepine ring system (6) are not known. The only available monograph on azepines refers to merely nine publications on these ring systems (84HC(1)236). 

A novel ring expansion of quinolines for the synthesis of benzoazepines was reported by Yadav and coworkers. Quinolines 76 (Scheme 34) were reacted with various diazocarbonyl compounds 77 in the presence of copper(II) triflate to generate the seven-membered azepine ring system 78 in good yields. Isoquinolines were also shown to undergo ring expansion under the same conditions <04CC2124>. 

Perophoramidine (18) shares the same connectivity as the communesins, but 18 contains a bis-amidine rather than the bis-aminal functionality present in 15-17. The trans- rather than the c/s-stereochemical relationship of the vicinal quaternary centers is another distinguishing feature. Moreover, 18 lacks the azepine ring system of communesin A, and 18 contains two chlorines on the aromatic ring [28]. 

B. Renfroe, C. Harrington, G. R. Proctor, and A. Rosowsky, Azepines. Part One, Ch. 1 Dibenzazepines and Other Tricyclic Azepines Ch. 2 Azepine Ring Systems Containing Two Rings... 

Many reactions of substituted diazepines and their fused derivatives frequently relate to a study of the functionality rather than being dependent on the presence of the azepine ring system, most particularly with reduced derivatives. Reaction of the unsymmetrical semicarbazones (110) <91JOC5203> gives the two selenodiazoles (111) and (112), the ratios of which show a solvent dependency (Equation (8)). 

The first step was the Pd-catalyzed formylation of the commercially available bromoindole derivative 193 using a procedure reported by Belter and co-workers (Scheme 4.2) 146). It was found to be necessary to protect to alcohol function with TMSCl in situ to avoid formation of a seven-membered lactone. The crude aldehyde 194 was directly converted with 195 to the W-t-butanesulfinyl imine 196 in 53% yield over two steps. Double protection of the alcohol and the aromatic amine function from 196 yielded the bis-tosylated Al-sulfinyl imine 197 in good yield. The Rh(I)-catalyzed addition of the newly developed MIDA boronate 198 (747) provided sulfonamide 199 in 78% yield and with high diastereoselectivity. Deprotonation of the sulfonamide function of 199 led to closure of the azepine ring system to furnish 200. Subsequent removal of the protection groups in 200 afforded the natural product (-)-176 in quantitative yield and with high optical purity. 

Coldham and coworkers reported a tandem condensation/cyclization/intramolec-ular cycloaddition cascade process to form fused tricychc amines, using azomethine ylides (derived from a-amino-acids or esters). This chemistry was apphed for the constmction of the pyrrolo[l,2-a]azepine ring system of the Stemona alkaloids (Scheme 4.20) [39]. Condensation of the aldehyde 96 bearing a dipolarophile (an... 

FIGURE 2 Examples of drug molecules containing azepine ring system. 

The conformation of the 1ff-azepine ring has stimulated much interest since a planar lff-azepine would possess a destabilizing antiaromatic 8jc-electron system.14,15 In fact, early... 

The parent cyclopent[Z>]-2 and cyclopent[c]azepine4 ring systems are known and have been fully characterized. Cyclopent[t/]azepine has also been reported54 but no full experimental details or properties of this system have been published. 

Compilations of UV data for 1-acyl- and 1-sulfonyl-l//-azepines are available.61 These systems display three major absorptions at 210-215, 240-247 and 285-330 nm. The weak, long wavelength band, which is thought to be due to interaction of the nitrogen lone pair with the triene system, often extends into the visible region and is responsible for the orange-yellow color of many 1-substituted 1//-azepines. 2,7-Disubstituted 1/7-azepines, in which the azepine ring is in the boat conformation, are colorless.61... 

The process of dehydrohalogenation has been used on several occasions to prepare cyclopent-azepine and indenoazepine ring systems. 

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 general, 1//-azepines are fragile ring systems which undergo facile ring contraction to arene derivatives under acidic, thermal, and photolytic conditions. 

In accord with experimental observations, SCFMO calculations indicate that an /V-acyl function should deactivate 5f/-dibenz[/>,/]azepine towards electrophilic substitution at the carbocyclic rings, and that substitution should occur preferentially at the CIO position.32 The calculated dipole moment (0.98 D) for 5f/-dibenz[A,/]azepine compares favorably with the measured value (0.96 D), and is expected for a nonplanar ring system.58... 

This reaction can be generally applied with equal success to other 2,6-dialkylphenols,4 many of which are commercially available. Although the procedure cannot be extended to phenol or o-monosubstituted phenols (aminophenols result6), it represents a facile synthetic method for obtaining a ring system heretofore relatively unavailable. The dihydroazepinones in turn are excellent starting materials for the preparation of other novel heterocyclic systems such as 2,3-dihydro-1 H-azepines,6 2-sub-stituted-3H-azepines,7 and derivatives of 2-azabicydo[3.2.0]hept-6-ene.8... 

Fozard and Jones (65JOC1523) have discussed the then hypothetical, maximally unsaturated ring system of pyrido[l,2-fl]azepine (1). Because a fully aromatic form of the parent substance must be excluded they expected some stabilization by a hydroxy group attached to the 10-position, in this... 

Other seven-membered ring systems to have been successfully /3-lithiated include 5//-dibenz[6,/]azepine and its 10,11-dihydro derivative (83JHC341 84JHC197). The 4,5-dilithio derivatives 196 and 197 react successfully with electrophiles such as dialkylamides and D20 to give 4-substituted derivatives. Mention of the lithiation of these systems has also occurred in the patent literature (71USP3624072). 

Extensive work has been carried out on the 1,7-electrocyclization of diene-conjugated nitrile ylides (324) leading to fused heterocyclic systems containing the azepine ring (325). Reactions of this type for all 1,3-dipoles have been reviewed (197,198). 

Medium-sized and large ring systems often show complicated conformational interconversions involving pseudorotations in one or even more conformational families. This makes stereochemical assignments in diastereomers rather difficult. Thus, very few systematic studies have been published. The situation is improved if such rings are embedded in polycyclic systems, or if they contain double bonds, which leads to restricted conformational mobility. An example is the differentiation of diastereomeric 2,3-dihydro-lf/-benzo[6]azepines 1 on the basis of y-gauche effects and on d(13C) and 3/H H values640. 

---