Aryl-2//-azepines

The reaction of an azepinium ion (3), generated in situ, with a number of aromatic substrates (benzene, anisole, phenol, furan and thiophene) usually gave aryl-2//-azepines [e.g. (4) from benzene] as the major products.7 In the case of reaction with pyrrole, however, a ring-opened compound (5) was the major product. Some condensed thiophenes have been shown8 to give products of substitution at C(l). For example, (6a) gave (6b) on diazo coupling. 

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). 

Poly-1,2-1//-azepines, produced by gas-phase photopolymerization of aryl azides yield, after oxidation, electrically conducting films.103 By photolyzing 4-(pcntyloxy)phenyl azide in the gas phase, a flexible polyazepine is produced which can be deposited directly as a thin polymer film onto a suitable surface. 

More recently, self-assembling 3//-azepine monolayers on a gold surface have been obtained by the photodecomposition of bis ll-[(4-azidobenzoyl)oxy]undec-l-yl disulfide.284 Other than some alkyl and aryl 177-azepine-l-carboxylates, which possess fungicidal activity, particularly against Sclerotium rolfsii,104 the unsaturated azepine systems surveyed in this section do not have any notable biological activity. 

Flash-vacuum pyrolysis of 3-alkyl-or 3-aryl-2-azabicyclo[3.2.0]hepta-2,6-dienes 5a-c, prepared by the action of a Grignard reagent (RMgX) on the 3-methoxy derivative 5 (R = OMe), furnishes mixtures of the 2- and 7-substituted 3//-azepines 6 and 7, respectively.113... 

Subsequently it was found140 that ethyl 2-alkyl-1//-azepine-1-carboxylates can be isolated from a mixture of isomeric 1//-azepines by stirring the mixture with potassium hydroxide in ethanol at room temperature. Apparently, this method, which is limited to 2-alkylated azepines, depends on the slower rate of hydrolysis (and subsequent decomposition of the resulting 1H-azepine-l-carboxylic acid) of the sterically hindered 1-(ethoxycarbonyl) group. Although the yields of l//-azepines are poor (4-7%, vide supra), the method provides access to otherwise difficult to obtain, isomerically pure 2-alkyl-1//-azepines. Under the basic hydrolysis conditions aryl 2-alkyl-l//-azepine-1-carboxylates undergo transesterification to the l-(ethoxycarbonyl) derivatives. 

The products from the thermolyses of other alkyl and aryl azidoformates in 1,4-di-tm-butylbenzene are unpredictable. In some cases, e.g. with cyclopropylmethyl, tert-butyl and 4-methoxyphenyl azidoformates, only the corresponding 3,6-di-/< rt-butyl-l//-azepines are... 

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... 

In contrast to the acyl- and sulfonylnitrenes described in this section, arylnitrenes produced thermally or photolytically from aryl azides, including those bearing strongly electron-withdrawing substituents (e.g., CN, N02, CF3), fail to promote ring expansion of arenes to 1H-azepines, although intermolecular substitution of electron-rich substrates, e.g. mesitylene and A.TV-dimethylaniline, have been noted.167... 

More surprising, in view of its poor electrophilic character, is that phcnylnitrene, generated by deoxygenation of nitroso benzene with triethyl phosphite in a mixture of benzene and 2,2,2-trifluoroethanol, yields 1-phenyl-1//-azepine (26), a rare example of a stable 1-aryl-lH-azepine.170... 

The thermal, and more importantly, the photolytic decomposition of aryl azides in the presence of nucleophiles, generally amines or alcohols, is the commonest method for preparing 3H-azepines. In fact, jV-phenyl-3//-azepin-2-amine (32, R = Ph), the first example of a 3//-azepine, was prepared by thermal decomposition of phenyl azide in aniline.32... 

The thermolysis of aryl azides in alcoholic solution has been used to prepare 2-alkoxy-37f-azepines. Thermolysis of 3-azidophenyl methyl ketone in methanol in a sealed ampule furnishes a mixture of the 6-acetyl- (36a) and 4-acetyl-2-methoxy-3//-azepine (37a) in superior yields to those obtained in the corresponding photolytic reaction.78 Other 3-substituted azides behave similarly, with a preference for the 6-substituted isomers 36, as is observed for azide photolyses in amine solutions. 

The synthesis of 3//-azepines by the photolysis of aryl azides in nucleophilic media is a much more efficient and versatile route than the thermolytic process. Initial studies involved photolysis of the aryl azides in an excess of a secondary aliphatic amine, and moderate yields of A, V-dialkyl-3//-azepin-2-amines 38 were obtained.35-1 72... 

Photolysis of aryl azides in amine solution, with a tertiary amine as cosolvent to promote stabilization of the singlet nitrene, has met with some success. For example, the yield of 2-piperidino-3 W-azepme. obtained by the photolysis of phenyl azide in piperidine, is increased from 35 to 58% in the presence of A A /V. /V -tetramethylethylenediamine (TMLDA).180 Also, an improved yield (36 to 60 %) of A,(V-diethyl-3W-azepin-2-amine (38, R = Et) can be obtained by irradiating phenyl azide in triethylamine, rather than in dicthylaminc, solution.181 Photolysis (or thermolysis) of phenyl azide in TMEDA produces, in each case, 38 (R = Et) in 40% yield.181 In contrast, irradiation of phenyl azide in aniline with trimethylamine as cosolvent furnishes jV-phenyl-377-azepin-2-amine (32, R = Ph) in only low yield (2%).35... 

There is evidence from a detailed study of the photolyses of 2-alkyl-substituted aryl azides 40 in diethylamine that A3,7V-diethyl-1 //-azepin-2-amines are formed as oxygen-sensitive, meta-stablc intermediates that can give rise to a variety of byproducts, including 5-acyl- A%V-diethyl-pyridin-2-amines and 6-alkyl-7-(diethylamino)-2//-azepin-2-ones 11 however, formation of these oxidation products can be avoided by refluxing the photolysate mixture with methanol prior to exposure to oxygen, in which case practicable yields of the /V,/V-diethyl-3W-azepin-2-amines 41 result. 

As expected of an unsymmetrically substituted aryl azide, the photolysis of 5-azidoindane (68) in diethylamine furnishes an unseparated mixture (31 % yield) of /V./V-diethyl-l, 6,7,8-tetrahyd-rocyclopent[J]azepin-2-aminc (69) and /Y,/V-diethyl-4,6,7,8-tctrahydrocyclopent[[Pg.151]

Early efforts to effect the photoinduced ring expansion of aryl azides to 3H-azepines in the presence of other nucleophiles met with only limited success. For example, irradiation of phenyl azide in hydrogen sulfide-diethyl ether, or in methanol, gave 17/-azepine-2(3//)-thione35 (5% mp 106—107 " O and 2-methoxy-3//-azepine (11 %),2 3 respectively. Later workers194 failed to reproduce this latter result, but found that in strongly basic media (3 M potassium hydroxide in methanol/dioxane) and in the presence of 18-crown-6, 17/-azepin-2(3//)-one was produced in 48% yield. In the absence of the crown ether the yield of azepinone falls to 35%. 

In contrast, aryl azides 86 bearing an ortho electron-withdrawing group, particularly a carbonyl function, in methanol solution ring expand upon photolysis in practicable yields to provide 2-alkoxy-3//-azepines 87 36,74,195 -197 shorter reaction times and improved yields are often obtained using a 1 1 alcohol/tetrahydrofuran mixture. 

Practicable yields of 5-substituted 2-methoxy-3//-azepines 94 can be obtained by photolysis of aryl azides 56 bearing an electron-withdrawing group para to the azide function, although irradiation times tend to be longer and, in general, yields lower than with the corresponding 2-substituted azides.197... 

The photolysis of aryl azides in water or aqueous tetrahydrofuran provides access to 1 //-azepin-2(37/)-ones. 136.197.199.202... 

Nucleophilic displacement of the butoxy group in 2-butoxy-3//-azepine (1) by the use of excess secondary amine is preferred by some workers64 to the photolysis or thermolysis of aryl azides, or the deoxygenation of nitro- or nitrosoarenes in amine solution, as a preparative route to Ar,Ar-dialkyl-3//-azcpin-2-amines, e.g. 2,... 

Curiously, the ring expansion fails in sulfuric, trifluoroacetic, trichloroacetic, and orthophos-phoric acid. The reaction is sensitive to substituents both in the TV-aryl group and in the 2-and 3-positions of the indole nucleus. For example, 3-methyl-l-phenylindole yields a mixture of 10-methyl-5//-dibenz[/t,/]azepine (34% mp 129-131X) and 2-mcthyl-l-phenylindole (57%). In contrast, 2-methyl-l-phenylindole and 2,3-dimethyl-l-phcnylindole fail to ring expand. The reaction also fails with electron-withdrawing groups (N02 and CF3) in the TV-phenyl ring. 

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. 

Tautomerism of benz- and dibenzazepines is much less common than with monocyclic azepines since, as pointed out in the introduction, with most of these bi- and tricyclic systems the number of tautomers in which the carbocyclic ring retains its benzenoid character is severely restricted. Rare examples in the benzazepine series are the thermal isomcrizations of butyl l-aryl-5//-2-benzazepine-5-carboxylates 1 (X = H, Cl, F) to their 3//-tautomers 2,7S and of 3-ethoxy-1-phenyl-5//-2-benzazepines 3 (R = Me, Bn) to the 1//-tautomers 4.240... 

Oxidation of 6-aryl-5//-dibenz[c e]azepinium bromides, e.g. 8, with hydrogen peroxide results in formation of bis(6-phenyl-6,7-dihydro-5//-dibenz[c.e ]azepin-7-yl)peroxide (9).92... 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

An interesting annelation reaction of allene-derived 13-dipoles with 3-(IV-aryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel iV-aryl-2,3-dihydro-4-ethoxycarbonylchromano[2,3-h]azepin-6-one system 39 (for example, R = Me, R1 = Cl) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023>... 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

These photoisomerizations can be solvent sensitive. For example, photolysis of the azepinone (42 R1 = aryl, R2 = Bu, R3 = H) in cyclohexane affords the azabicycloheptadiene (43 R1 = Ar, R2 = Bu , R3 = H) in 80% yield. Irradiation in methanol solution, however, affords a mixture of the two isomeric enols of the cyclopentenone (44 60%), and only 5% of the bicycle (43) (81JOC4077). Apparently, in aprotic solvents the azepine behaves photo-lytically as a heterocyclic conjugated triene, whereas in methanol its /3,-y- unsaturated ketone character predominates. 

The oxidation of AT-substituted 5//-dibenz[6,/] azepines with MCPBA is complex and depends upon the nature of the N-substituent. AT-Acyl derivatives do not form the N-oxide but suffer epoxidation of the 10,11-bond. AT-Aryl derivatives undergo hydroxylation of the phenyl ring, whereas N-alkyl congeners, with the exception of the AT-methyl compound, yield mixtures of diphenylamines and acridones. The N-oxide is obtained from the A/-methyl derivative along with ring-opened and ring-contracted products (81CPB1221). 

The additions of alkyl or aryl silyl chlorides to 1 -ethoxycarbonyl- 1H-azepine in HMPA solution in the presence of magnesium proceed via anion radicals to yield trans adducts... 

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