Azepine ring

A radically different course is followed when the reaction of 2-alkyl-substituted thiazoles is periormed in methanol or acetonitrile (335), 2 1 adducts containing seven-membered azepine rings (91) are being formed in which two of the original activated hydrogen atoms have altered positions (Scheme 55). A similar azepine adduct (92) was obtained by... 

Stereoselective azepine ring formation via intramolecular ene reaction 97YGK725. 

Reaction of 2-(A -alkyl-A -benzylamino)- and 2-[A -(rraM-crotyl)-A -ben-zylamino]-3-formyl-4/7-pyrido[l,2-n]pyrimidin-4-ones (260, R = H, Me) with tosylamine gave compounds 268 via compounds 266 and 267 (96T13097). The results of kinetic studies and MP3 calculations on the 3-formyl derivatives 252, 260 and the imines 262, 263 suggested a concerted nature for azepine-ring formation. 

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... 

Although theseazepin-2-onesexhibitdeshieldedprotonresonances(<5 = 7.8 8.2), with an ortho coupling for the 5,6-unsubstituted derivative of J5 6 = 10 Hz, an X-ray structural analysis of ethyl 7-(4-bromophenyl)-3-methoxy-2-oxo-6-phenyl-27/-azepine-4-carboxylate reveals a non-planar azepine ring 48 53 3,5-Dihaloazepin-4-ones have been detected recently in the photolysis of 4-azido-2,6-dihalophenols at 12-14 K.286... 

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... 

However, if the azepine is C-monosubstituted, e.g. 14, or unsymmetrically substituted, then two isomeric 2-azabicycloheptadienes, e. g. 15 and 16, may result corresponding to electrocyclic ring closure involving C2-C5 or C4-C7 of the azepine ring. In practice, the ratio of the two isomers formed (which may be separated by vapor phase chromatography) varies with the position of the substituent.236 In contrast, irradiation of methyl 2,5-di-tm-butyl-l//-azepine-l-carboxylatein methanol yields only methyl 3,5-di-tert-bulyl-2-azabicycIo[3.2.0]hepta-3,6-diene-2-carboxylate (81 %).70... 

Complete reduction of the azepine ring to hexahydroazepine has been effected with hydrogen and palladium,40 or platinum,135 239 catalysts. For example, ethyl 1 f/-azepine-l-carboxylate is reduced quantitatively at room temperature to ethyl hexahydroazepine-l-carboxylate (92% bp 118 —120 3C).134 136 TV-Phenyl-S/Z-azepin -amine (1), however, with platinum(IV) oxide and hydrogen in methanol yields the hexahydroazepine 2 in which the amidine unit is preserved in the final product.34 The same result is obtained using 5% palladium/barium carbonate, or 2 % palladium/Raney nickel, as catalyst. 

Methyl 3,6-di-fert-butyl-1 //-azepine-1 -carboxylate (8), on heating with one equivalent of methyl azidoformate, yields a separable mixture of 2,6-and 2,8-diazabicyclooctadienes 10 and 11.145 Initial addition of the nitrene to C4-C5 of the azepine ring, followed by a [1,3]-C or [1,3]-N shift in the resulting azahomoazepine 9, accounts for the products. 

The effect of substitutents at the C3 and C6 positions of the azepine ring is much more dramatic in that they force the 1//-azepine into a competing [6 + 2] Tt-cydoaddilion at the Cl —Cl positions.6 1 In fact, at room temperature [6 + 2] cycloaddition by a kinetically controlled, non-concerted, ionic process appears to be dominant, since on treating a mixture of ethyl 3,6-dimethyl- and ethyl 2,5-dimethyl-l//-azepine-l-carboxylate with less than a molar equivalent of ethenetctracarbonitrile, only the [6 + 2] cycloadduct 10 of the 3,6-dimethyl-l//-azepine is formed. 

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... 

Bromination of 4-methyl-5-propanoyl-177-1-benzazepine (1) takes place at the 8-position in unspecified yield.81 Addition of bromine to the azepine ring is not observed. 

Likewise, amine functions on the azepine ring at an unsaturated carbon center behave as enamines and undergo hydrolysis under both acid and alkaline conditions to the benzazepinones.15,64 8084 However, hydrolysis of dimethyl l-acetyl-5-piperidino-l//-l-benz-azepine-3,4-dicarboxylate(18) yields not the benzazepinone but the tautomeric 5-hydroxy derivative 19.13 Presumably, the enol form is stabilized by intramolecular hydrogen bonding. 

Arylation of the azepine ring has been carried out by treating either 9-chloro-6-methoxy-5/7-pyrido[2,3-c]azepine (50, X = Cl) as a mixture with the isomeric 9-chIoro-6-methoxy-7A/-py-rido[2,3-c]azepine (see Section 3.2.1.5.5.1.). or, better, the 6,9-dimethoxy derivative (50, X = OMe) with phenyllithium.152 In the former case, a mixture (20%) of the 9-phenyl-5//-and 9-phenyl-7//-pyrido[2,3-c]azepine is formed. 

The oxidation of dimethyl 3-methyl-3//-3-benzazepine-2,4-dicarboxylate (1) with potassium permanganate in acetone solution brings about destruction of the azepine ring and formation of phthalic anhydride (2).24... 

As part of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted tetrahydro-li/-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported <06JOM5406>. 

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>. 

Construction of the azepine ring by C-C bond formation. The Heck-type cyclization of amides 11, easily available by amide bond coupling (EDCI, DMAP) between the corresponding indolo- and pyrrolo-[2,3- 7]p)uidine-carboxylic acids and 2-iodobenzylamine, is effective in the presence of Pd(OAc)2/PPh3 catalyst and silver carbonate base and leads to excellent yields of the corresponding azepinones 12 (Equation (1) (2005TL8177)). 

Construction of the azepine ring by C-N bond formation. Indole 26,... 

Several azepine ring constructions have been reported using palladium catalyzed C-C bond formation. Palladium catalyzed cyclizations of substituted tryptamine derivatives 73 lead to benzo[d]pyrrolo[l,2-a]azepinones 74 (Equation (8) (2000JMC1050)). 

Construction of the azepine ring by C-N bond formation. Aranapakam et al. synthesized 5,10-dihydro-4H-benzo[l7]thieno[2,3-e]azepine 111 and 4H-benzo[ 7]thieno[3,2-e]azepin-10(9H)-one 113 (X = CO) starting from the corresponding tributylstannyl derivatives 110 and 112, which react with 2-nitrobenzyl bromide and [(Ph)3P]4Pd. Sequential deprotection and reductive cyclization were carried out in one step with zinc and aqueous acetic acid (Scheme 22 (1999BMCL1733)). 

Semiempirical and molecular mechanics calculations have been widely used. Thus, conformation of indolo benzazepine 423 (Figure 8) with its conjugated benzo and indole rings has been studied by molecular mechanics (MMX force field). Its planarity was estimated from a calculation of dihedral angle Ti 2 3 4 the value of ca. 22° is due to strain as contributed by azepine ring. This characteristic was further compared to that of the open-chain and six-membered... 

As already noted, there are drugs found among benzodiazepine derivatives that have expressed anxiolytic action and that lack or have poorly expressed sedative-hypnotic effects, which are called daytime tranquilizers. Medazepam, a representative of the daytime tranquilizers, is a drug that differs from diazepam only in the absence of a carbonyl group in the seven-membered 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 . ... 

Various efforts have been made to produce the Balanol nucleus, a chiral azepine ring, and many of the synthetic routes include a Beckmann rearrangement to produce the... 

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). 

Several therapeutic agents are based on phthalazinone nuclei, in which the hydrazide carbonyl group persists in unmodified form. Reaction of keto-acid (69-1) with hydrazine leads to the phthalazinone (69-2). Alkylation of the hydrazide nitrogen with 2-(chloroethyl)-A-methylpyrrolidine (69-3) surprisingly leads to the incorporation of a seven-membered azepine ring rather than the expected ethylpyrroldine. This can be explained by keeping in mind that it is likely that the... 

Chemical shifts for the azepine ring protons, as might be anticipated from their non-planar, polyene character, lie in the vinyl proton region (5 4.5-6.8 p.p.m.). Chemical shifts and coupling constants of representative examples of azepines and their hydro, oxo, benzo and dibenzo derivatives are listed in Table 2. 

Ring inversion of the azepine ring between the two stable boat forms has been studied extensively by H NMR spectra Early work on 2-anilino-3//-azepine demonstrated that at 25 °C the methylene group appears as an AX system (7(HAHB-HX) 7 Hz), whereas at -75 °C in acetone- 6 an ABX system (7ab H Hz, 7ax 6 Hz, JBX 8 Hz) is evident... 

Stable cations, anions and radicals derived from azepines are rare species, although many ring contractions and some valence isomerizations appear to involve prior formation of a cationic species, especially in those partially saturated systems in which an enamine moiety forms an integral part of the azepine ring. It is only recently that azepine anions have been generated and their synthetic potential exploited (Section 5.16.3.6). 

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