Benzene azepine ring

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

Direct electrophilic substitution of benz- and dibenz-azepines remains relatively unexplored. Most substituted benzazepines have been prepared from benzene precursors bearing the desired substituents (74AHC(17)45). The bulk of the reported electrophilic substitutions have been carried out on 5//-dibenz[6,/]azepine (74CRV101), MO calculations on which predict that substitution should occur at the 2- and 4-positions, i.e. para and ortho to the azepine ring nitrogen. These predictions are borne out by Friedel-Crafts alkylation and acylation studies, although it is apparent that a second alkyl group enters at the 8- rather than at the 4-position. Formylation under Vilsmeier conditions yields the 2-aldehyde. As noted earlier (Section 5.16.3.4), however, the 10,11-dihydro system exhibits different behavior and acylates at the benzylic 10,11-positions. Nitration with mixed acids of the... 

Compounds of the benzene oxide and benzene imide types are tautomeric with, and generally exist predominantly as, the seven-membered oxepin and azepine rings (see Sections 2.5.5.2 and 3.5.2.2). For arene oxides and related derivatives see . 

Perfluorotetramethylthiadiphosphanorbornadiene and bis(trifluoromethyl) thiadiphosphole can be prepared by thermolysis of an adduct of methanol and hexakis(trifluoromethyl)-l,4-diphosphabarrelene with sulfur [113] (equation 23) Pyrolysis of the adduct of hexafluorinated Dewar benzene and phenyl azide results in ring expansion giving azepine, which photochemically yields an intramolecular 2-1-2 adduct, a good dienophile for the Diels-Alder reaction [114, //5] (equation 24) Thermolysis of fluonnated derivatives of 1,5-diazabicyclo-... 

Problems arise in the preparation of substituted l//-azepines with (alkoxycarbonyl)nitrenes as nitrene attack on a mono- or disubstituted benzene ring is not generally regioselective, and with toluene, 04 34-136139 144 o- and p-xy ienes,134-139 p-cresoi,134 chlorobenzene104-134 136 and biphenyl,104 136 mixtures of 1//-azepine-1-carboxylates of undetermined composition are produced. 

Ring expansion of the benzene ring of a calix[6]arene to a 1 //-azepine in 14% yield by photolysis of an aryl azide confined in the calix structure has been reported.294... 

The highly electrophilic 1,3,5-triazinylnitrene generated by photolysis of 2-azido-4,6-dimethoxy-l,3,5-triazine (24) does, however, bring about ring expansion of benzene to l-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1//-azepine (25) in moderate yield.168... 

Whereas the production of arylnitrenes by the deoxygenation of nitrosobenzenes or nitro-benzenes by trivalent phosphorus reagents and their subsequent intramolecular ring expansion to 3//-azepines are well-known processes, the corresponding intermolecular reactions to form 1//-azepines have been exploited only on rare occasions and appear to be of little preparative value. For example, the highly electrophilic pentafluorophenylnitrene, obtained by deoxygenation of pentafluoronitrosobenzene with triethyl phosphite in benzene solution, produced a low yield (2-10%) of l-(pentafluorophenyl)-l//-azepine, which was isolated as its [4 + 2] cycloadduct with ethenetetracarbonitrile.169 With anisole as the substrate l-(pentafluorophenyl)-l//-azepin-2(3//)-one (16% bp 128 —130 C/0.4 Torr) was obtained. 

Interestingly, 3-(cyclohepta-2,4,6-trienyl)-3.//-azepine (20) in refluxing benzene undergoes a [1,5]-H shift and isomerization of the azepine, rather than the cycloheptatrienyl ring, to yield the 6-(cyc ohepta-2,4,6-trienyl)-3//-azcpine (21).118 A mechanistic rationale for this highly selective [1,5]-H shift has been discussed.118... 

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... 

Treatment of ethyl 1 W-azepine-l-carboxylate with palladium(II) acetate in benzene, or in an aprotic solvent, results in ring contraction (see Section 3.1.2.4.) or ring opening (vide infra), respectively, however, with palladium(II) acetate in acetic acid ethyl 2,3-diacetoxy-2,3-dihydro-l//-azepine-l-carboxylate (6) is formed as the major product along with ( , )-hexa-2,4-dienedial.243... 

Nitroso-5//-dibenz[/>,/]azepine (9, R = NO) is relatively stable to photolysis under argon, whereas in benzene solution in the presence of oxygen, irradiation induces an oxidative Fischer -Hepp-type rearrangement to 2-nitro-5//-dibenz[6,/]azepinc (10, R = N02), accompanied by ring contraction to acridine-9-carbaldehyde184 (see also Section 3.2.2.4.). 

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). 

The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (di-azepine) at positions 1 and 4 (Fig. 30.1). Of the 2,000 benzodiazepines that have been synthesized, approximately 15 clinically useful compounds are on the market in the United States (Table 30.1). 

As expected, annulation to one or two benzene rings increases the overall stability of the azepine system (Section 5.16.1.2). Even so, some systems, e.g. (4) and (9), are too unstable as the NH tautomers to permit isolation, and as yet are known only as the oxo or hydro derivatives or, as in the case of the dibenzazepine (9), as the more stable fully benzenoid 5//-tautomer. 

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 ring expansion of arenes by electron-deficient singlet nitrenes is by far the most versatile synthetic route to 1H -azepines. The first l//-azepines were prepared independently in 1963 by Hafner, and by Lwowski, and their coworkers. They found that ethoxycarbonyl-nitrene (Scheme 26, path a R=C02Et), generated by photolysis of ethyl azidoformate, adds to benzene to give initially the unstable azanorcaradiene (227), electrocyclic ring... 

Caprolactam [105-60-2] (2-oxohexamethylenimine, hexahydro-2.fi-azepin-2-one) is one of the most widely used chemical intermediates. However, almost all of the annual production of 3.0 x 106 t is consumed as the monomer for nylon-6 fibers and plastics (see Fibers survey Polyamides, plastics). Cyclohexanone, which is the most common organic precursor of caprolactam, is made from benzene by either phenol hydrogenation or cyclohexane oxidation (see Cyclohexanol AND cyclohexanone). Reaction with ammonia-derived hydroxylamine forms cyclohexanone oxime, which undergoes molecular rearrangement to the seven-membered ring 8-caprolactam. 

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