Azepines aromaticity

Anastassiou has summarized in two reviews the knowledge about IH-azonine (41a) [72ACR281 78AHC(23)55]. Compound 41a as well as its salts (N M" ) are aromatic compounds which exist as such and not as imine polyenic forms. Tliis compound demonstrates a valence isomerism 41a/41b similar to that of l//-azepine (14a/14c see Section II,A,1) the transformation 41a 41b occurs upon irradiation. 9-Azabicyclo[6.1.0]nona-2,4,6-triene 41b displays no tendency to thermal isomerization to 41a at ambient temperature (72ACR281). 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

It is likely that initially the open-chain adducts 353 and 354 are formed by the addition of an amino group either to the carbonyl function or to the triple bond, whereupon these intermediates close up to the azepines 355 and their bis-imine tautomers 356. In the H NMR spectra, the methylene protons of 356 are at 2.85-2.97 ppm, whereas the methyl protons are fixed at 2.20-2.27 ppm. The IR spectra show absorption bands corresponding to the aromatic ring (1600 cm ) and to the diazepine cycle C=N double bonds (1580 cm ). However, there are no bands of... 

Oxepin and its derivatives have attracted attention for several reasons. Oxepin is closely related to cycloheptatriene and its aza analog azepine and it is a potential antiaromatic system with 871-elcctrons. Oxepin can undergo valence isomerization to benzene oxide, and the isomeric benzene oxide is the first step in the metabolic oxidation of aromatic compounds by the enzyme monooxygenase. 

The cyclopentazepine systems are often1-5 referred to as 4-aza-, 5-aza-, and 6-azaazulene, respectively. Confusingly, the cyclopent[a]azepine 8a, which is more correctly known as 1ff-pyrrolo[l,2-a]azepine, has been referred to as 4-azaazulene6 and as 3a-azaazulene.7 Only the carbonyl derivative 8b of this nonconjugated system is included in this section since it can be represented as the fully conjugated, aromatic, dipolar structure 9.6... 

The early unsuccessful search for aromatic character in 2//-azepin-2-one (14) and 47/-azepin-4-one (15), the 6n-monoaza analogs of tropones, has been surveyed.46... 

X-ray crystallographic studies are available on the ethoxy compound 1858 and on N,N-dimethylcyclopent[c]azepin-3-amine(19).59 The former is a fully conjugated, planar, 14k, non-benzenoid aromatic system, while the latter is virtually planar and, on the basis of bond length measurements, is best represented as the dipolar mesomer 19B. 

On the basis of ab initio MO studies on the nitrenium ion 23 derived from 1//-azepine, it has been concluded that the singlet nitrene is a planar, fully conjugated C2v system with substantial 67r-aromatic character. 

Methylation of indeno[l,2-r/]azepin-4(3//)-one (22) with iodomethane under phase transfer conditions produces the A-methyl derivative, whereas ethylation with Meerwein s reagent yields purple crystals of the indeno[l, 2-r/Jazepine 23, a 147r-aromatic system.57 1 l-Bromo-4-ethoxyin-deno[l,2-r/]azepine (69% mp 143-144°C) can be prepared similarly. 

In acid solution 1-acyl-1//-azepines and alkyl l//-azepine-l-carboxylates undergo rapid aromatization to A-arylcarbamates,115,139,142 whereas 1/Z-azepine-l-carbonitrile suffers quantitative rearrangement and hydrolysis to phenylurea.163 Rearrangement of ethyl l//-azepine-l-carboxylate to ethyl A-phenylcarbamate is also rapid (5 min) and quantitative with boron trifluoride-diethyl ether complex in benzene.245... 

On heating, the dichlorooxazolo[3,4- ]azepine 26, for which dimerization is prevented by the chloro groups, undergoes ring contraction and aromatization, involving a [l,2]-chlorine shift, to 5,8-dichloro-l,4-dihydro-2//-3,l-benzoxazin-2-one (27).11,153... 

Dimerization, however, is subject to steric restraint and is inhibited by substituents at the 2-, 4- and 7-positions.115 In such cases thermolysis of the l//-azepine leads to aromatization to the corresponding N-arylearbamate. 

X-ray analysis of 2-methoxy-4-hydroxy-5//-l-benzazepin-5-one (a benzazatropolone), prepared by methylation of the corresponding 4-hydroxy-l-benzazepin-2,5-dione with Meerwein s reagent, demonstrates the presence of a planar seven-membered ring but, in contrast to tropolone, little 71-electron delocalization.17 Likewise, ll//-dibenz[f>,e]azepin-ll-ones display no significant aromatic character.18 In contrast, 7-chloro-8//-thieno[3,2-c]azepin-8-one (12) has azepine ring hydrogen resonances at 8.7 and 9.02 ppm that indicate a substantial contribution from the polar zwitterionic mesomer 13.19... 

The isomeric pyridazino[4,5-6]azepine 19 is obtained directly during the decomplexation of the [4 + 2] adduct 17 formed from tricarbonyl(ethyl +17/-azepine-l-carboxylate)iron and 1,2,4,5-tetrazine-3,6-dicarboxylate, with trimethylamine A-oxide.113 Surprisingly, decomplexation of adduct 17 with tetrachloro-l,2-benzoquinone yields only the dihydro derivative 18 (71 %), aromatization of which is achieved in high yield with trimethylamine A-oxide in refluxing benzene. 

Seven-membered conjugated systems having a hetero atom, heteropin (7), consist of 177-azepine (7, X = NH), oxepin (7, X = O), and thiepin (7, X = S). Since these divalent hetero atoms are isoelectronic with the ethylenic linkage, heteropins might be considered to be 8tt electron heteroannulenes which are not aromatic but antiaro-... 

In connection with the chemistry of the reactive transient species, nitrene, the chemistry of azepines is well documented u. Also, the chemistry of oxepins has been widely developed due to the recent interest in the valence isomerization between benzene oxide and oxepin and in the metabolism of aromatic hydrocarbons 2). In sharp contrast to these two heteropins, the chemistry of thiepins still remains an unexplored field because of the pronounced thermal instability of the thiepin ring due to ready sulfur extrusion. Although several thiepin derivatives annelated with aromatic ring(s) have been synthesized, the parent thiepin has never been characterized even as a transient species3). 

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... 

Q Which of the following heterocycles conform to the Huckel rule (4h +2) for aromaticity (i) furan (ii) l//-azepine (iii) pyrylium perchlorate [chlorate(VIl)] ... 

Reduced and partially reduced azepines are more common. Perhydroazepine (hexamethylenimine) was first prepared in 1905 and chemically it behaves as a typical secondary amine (B-67MI51600). Its 2-oxo derivative (caprolactam) is a bulk chemical and is of great industrial importance as an intermediate in the manufacture of nylon. Many oxo and dioxo derivatives of azepines and benzazepines have been prepared, often with difficulty, in a mainly fruitless search for aromatic properties in these azatropone and benz-azatropone systems (see Section 5.16.3.1.2). 

One of the facets of azepine chemistry that has attracted organic chemists over the past two decades has been the synthesis of, and search for aromatic character in, the so-called azatropones and azatropolones. To this end all the monocyclic azepin-2-, -3- and -4-ones, several diones, and their benzo and dibenzo derivatives have been prepared. 

Dimerization of lff-azepines is an extensively studied phenomenon and involves a temperature dependent cycloaddition process. At low (0°C for 1 R = Me) or moderate (130 °C for 1 R = C02R or CN) temperatures a kinetically controlled, thermally allowed [6 + 4] dimerization to the exo -adduct (73) takes place, accompanied by a small amount (<10%) of symmetrical dimer (74). The latter are thermodynamically favored and become the major products (83%) when the Iff-azepines are heated briefly at 200 °C. The symmetrical dimers probably arise by a non-concerted diradical pathway since their formation from the parent azepines by a concerted [6+6]tt cycloaddition, or from dimer (73) by a 1,3-sigmatropic C-2, C-10 shift are forbidden on orbital symmetry grounds. Dimerization is subject to steric restraint and is inhibited by 2-, 4- and 7-substituents. In such cases thermolysis of the lif-azepine brings about aromatization to the correspondingly substituted JV-arylurethane (69JA3616). 

Partially unsaturated azepines, like the fully conjugated systems, tend to be unstable in acid solution and undergo either rearrangement or ring contraction, generally to an aromatic system. Protonation takes place at nitrogen or, as in those hydroazepines in which delocalization of the nitrogen lone pair is possible, at the /3 -carbon of the enamine system. 

Huisgen found that 2-amino-3H-azepines are unstable under normal acylating conditions. Schotten-Baumann benzoylation, for example, brings about aromatization and, ultimately, formation of 2-(benzamido)diphenylamine, whereas p-nitrobenzoyl chloride in cold pyridine yields 2-(p-nitrophenyl)-l-phenylbenzimidazole. Benzenesulfonylation, however, proceeds normally at the exocyclic nitrogen. The mechanistic rationale for these ring contractions is outlined in Scheme 8 (b-69MI516oo). 

As mentioned in Section 5.16.3.2.2 phenanthroazepine (63b) with strong base (Bu OK) isomerizes to the AH-tautomer (a 3H-azepine) whereas the benzazepine (63a) in which a similar proton shift would involve loss of aromatic character in the solitary benzene ring, resists all isomerization attempts (74JOC3070). 

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>. 

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