1 //-Benz azepines

Chloro-l,4-dihydro-9-methylnaphthalen-l,4-imine is converted into isomeric dihydrocyclo-but[(j]indoles by direct photolysis, which are in turn converted into 6- and 9-chloro-1-methyl-1//-benz[/)]azepines upon heating in toluene. The azepines are converted back into the dihydrocyclo-but[/)]indoles by light, from which it has been postulated that the azepines may be the primary products in the reaction <85TL2827>. The isomerization of a number of l,4-dimethyl-9-halogeno-l,2,3,4-tetrahydro-l,4-iminonaphthalenes to 2,3,4,5-tetrahydro-l//-benz[/>]azepines by AgBp4 in benzene/methanol mixtures has been reported <86TL407i>. Under similar conditions, the 1,4-dihydro-derivatives are converted into quinolines. 

Thermolysis of the vinyl azide 11 in toluene furnishes a mixture of ethyl 2-phenyl-l//-3-benz-azepine-4-carboxylate(12), ethyl 4-(2-phenylvinyl)indole-2-carboxylate(13) and ethyl 1-benzyl-isoquinoline-3-carboxylate (14).82... 

The dehydrogenation of 2,3-dihydro- and 2,5-dihydro-l//-l-benzazepines to 3//-l-benz-azepincs with heterocyclic enamines in the presence of boron trifluoride diethyl ether complex has been achieved in moderate yields (30-35%).241 In contrast, electrochemical oxidation of 2,5-dihydro-1 H- -benzazepines in buffered acetic acid solution furnishes initially 5//-l-benz-azepines in 35-45% yield.242... 

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. 

In contrast to the 3-methoxy derivative (see Section 3.2.2.5.3.), the 3-isopropoxy-l//-2-benz-azepine 1 on treatment with sodium propan-2-olate undergoes dehydrobromination to the propenyl derivative 2.80... 

In a similar manner, bromination, dehydrobromination and amination of l-tosyl-l//-l-benz-azepin-3(2/7)-one yields the 2-amino-3//-l-benzazepin-3-one 10, which condenses with ben-zene-1,2-diamine to give 6//-l-benzazepino[2,3-6]quinoxaline (11).27... 

When the reaction is carried out on l-acetyl-3-piperidinoindole, the tricyclic intermediate corresponding to (255) can be isolated (78AHC(23)263, 80JOC462). Enhanced yields of benz-azepines are reported by carrying out the cycloadditions under high pressures (80H(14)1959, 81H(16)1367). 

A new method, shape signatures, in the area of computer-aided molecular design has been studied <2003JME5674>. The method has been demonstrated to work well in selecting molecules on the basis of shape and polarity and has been applied to a receptor-based strategy. Dibenzo[ /]thiepine appears in the hit list for 57/-benz[ /]azepin. 

Troj nek et al. found that the thermal decomposition of narceineimide methiodide in the presence of aqueous potassium hydroxide affords a mixture of stereoisomeric narceoneimides (148) along with 10,11-methyl-enedioxy-3,4,12-trimethoxy-7,8-dihydro-5//-isoindolo[l,2-ft][3]benz-azepine-5-one (149), which is identical with the oxidized red product... 

The dimeric alkaloid stepionine was isolated from Stephania japonica Miers. (Formosa) (723). Reductive fission transforms it into the 3-benz-azepine derivative, which is closely related to the rhoeadane alkaloids. It has also been prepared synthetically (724). 

Treatment of the /-butyl formamidine (72) with /-butyllithium followed by an electrophile produces the tetrahydroazepine derivatives (73) <85JOC10I9>. Typical electrophiles are n-propyl iodide, trimethylsilyl chloride, and benzyl bromide. 2,3,4,6-tetrahydro-17/-benz((>]azepines <93JOC6538> afford the corresponding 2-alkyl-dihydro derivatives together with the product from o-alkylation in the aromatic ring. iV-Boc derivatives give an even better yield of the 2-alkyl derivative, which is in marked contrast to the five- and six-membered compounds, where the sole product from the iV-Boc... 

Tietze and Schimpf have demonstrated that palladium-catalyzed Heck-type cyclization offers a viable route to 2,3,4,5-tetrahydro-l/7-benz[( ]azepines <938876,94AG(E)1089>. In the example shown in Equation (15), the product is a mixture of isomers. 

The synthesis of benzazepines by the acid-catalyzed cyclization of 7 (-(2-arylethyl)-7 (-methyl-2-sulfinylacetamides is a convenient alternative to this acid-catalyzed cyclization. Thus treatment of the amide (172) (Equation (17)) with trifluoracetic anhydride affords the benz(. This method has been used in a first synthesis of the benzopyranobenzazepine alkaloid ( +)-clavizepine <94SL49>. 

Subjecting acetanilides to the conditions of the Vilsmeier-Haack reactions is an effective method for the preparation of quinolines <8iJCS(Pi)i537>. On the other hand, if the phenacetanilide of anthranilic acid is subjected to the identical reaction conditions, 4-dimethylamino-3-phenyl-5H-benz[()]azepine-2,5-dione (189) is formed in high yield <84S349>. The phenyl group of anthranilic acid may be replaced by thienyl and pyridyl without loss in the efficiency of cyclization. 

In extending this reaction to naphthalene analogues, Kubo et al. have demonstrated that benz-azepine formation is the predominant reaction for 7V-methyl-l,2-naphthalenedicarboximide, but the 2,3- and 1,8-isomers are characterized by oxetane formation, an observation which has been attributed to the differing natures of the respective S,xn singlet states <86BCJ19l>. 

Substituted 7,12-dihydroindolo[3,2-c(][l]benzazepin-6(5/0ones 2a and 2b were first reported in 1958 by MacPhillamy et al. [33] as the last intermediate in an 11-step synthesis of 4-ethyl-5,6,7,12-tetrahydro-2-methylindolo[3,2-t/][l]benzazepine. In 1992, Kunick reported the preparation of six indolo[3,2-d][l]benzazepin-6(5/f)ones [34] in a three-step procedure. The crucial step was the decarboxylation reaction of 2,3-dihydro-5-hydroxy-2-oxo-l/7-benz[(t]azepin-4-carboxylic acid ethyl ester into 3,4-dihydro-lH-benz[ ]azepin-2,5-dione, which made possible the subsequent Fischer indole synthesis, with formation of the desired 7,12-dihydroindolo[3,2-fiT [l]benzazepin-6(5/f)ones. 

C20H21CIN2O4, Dimethyl-1-p-chlorophenyl-3,4-propano-4,5,6,7-tetra-hydroindazol 5,5-dicarboxylate, 46B, 280 C20H21NO4, Dimethyl 4,5,10,11,12,12a-hexahydroindolo[1,7-cd]benz-azepine-7,8-dicarboxylate, 44B, 260 C2oH22BrN30, Dimidium bromide, 40B, 278... 

Benz[l,2-e][l,3]oxazin[3,4-a]azepin-6-one (15) is cleaved rapidly in cold ethereal ethylamine to /V.A-diethyl-2-(2-hydroxyphcnyl)-l//-azepinc-1-carboxamide (90% mp 121 -122°C), whereas acidic hydrolysis yields the intramolecularly hydrogen bonded 2-(2-hydro-xyphenyl)-3//-azepine (16).156... 

An X-ray crystal structure of 7-methoxy-5//-dibenz[c,c]azepine reveals that the seven-mem-bered ring is in the boat conformation.7 Likewise, X-ray structural determinations of 2-morpho-lino-5H-d benz.[A/]azepi ne,7 and 5//-dibenz[/>, /]azepi ne.1 " 11 and its 5-acyl derivatives,12 in-... 

A detailed study of the dehydrogenation of 10.1 l-dihydro-5//-benz[6,/]azcpinc (47) over metal oxides at 550 C revealed that cobalt(II) oxide, iron(III) oxide and manganese(III) oxide are effective catalysts (yields 30-40%), but formation of 5//-dibenz[7),/]azepinc (48) is accompanied by ring contraction of the dihydro compound to 9-methylacridine and acridine in 3-20 % yield.111 In contrast, tin(IV) oxide, zinc(II) oxide. chromium(III) oxide, cerium(IV) oxide and magnesium oxide arc less-effective catalysts (7-14% yield) but provide pure 5H-dibenz[b,/]azepine. On the basis of these results, optimum conditions (83 88% selectivity 94-98 % yield) for the formation of the dibenzazepine are proposed which employ a K2CO,/ Mn203/Sn02/Mg0 catalyst (1 7 3 10) at 550 C. 

An elegant extension of these ring expansions involving diazidonaphthalenes has been reported. Early results on the photolysis of 1,8-diazidonaphthalene (14) indicated the formation of benz[t d]indazole (17).176 However, it has since been found that photolysis of the diazide in sodium methoxide-methanol/dioxane solution for a short period (20 -40 min) yields, in addition to the benz[c,d]indazole (17, 40%), a mixture of 9-azido-l-methoxy-5//-2-benzazepine (15 15-20%) and l,10-dimethoxy-5,5a-dihydroazepino[3,4-c]azepine (16 10-15%).117... 

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... 

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). 

Recently, a new reactivity index has been proposed (80H(14)1717> which predicts accurately the site selectivity of photocyclization of substituted cycloheptatrienes to their bicyclic valence tautomers. Unfortunately, application of the method to substituted lH-azepines is far less successful. For example, for 2-methyl-l-methoxycarbonyl-lH-azepine (37 R = 2-Me) AGrs values for C-2—C-5 and C-4—C-7 cyclization are calculated as 0.093 and 0.040 kJ mol-1, respectively, i.e. predicting the 1-methyl isomer (39) as the major product. Experimentally, however, the reverse is true, the yields being 93.5% for 3-methyl (38 R = Me) and 6.5% for 1-methyl (39 R = Me). The corresponding photoinduced valence isomerizations of 1-benzazepines to 3,4-benz-2-azabicyclo[3.2.0]hepta-3,6-dienes (38a) have been recorded (80JOC462). These isomerizations have also been achieved thermally in the presence of silver ion (80TL3403). 

Examples of electrophilic substitution (other than protonation) at the heterocyclic ring of benz- and dibenz-azepines appear to be confined to a few Vilsmeier reactions. 8-Chloro-l//-l-benzazepin-2-one with a mixture of DMF and POCl3 yields the 2,8-dichloro aldehyde (106) (72CPB1325). Under similar conditions Ar-mesyl-4,5-dihydro-3//-3-benzazepine formylates at the 1-position (107 R1 = CHO, R2 = H) (71BSF3985). In contrast, (V-mesyl-1,2,4,5-tetrahydro-3/7-3 -benzazepin-1 -one yields a mixture of the 1-chloro dihydro compound (107 R1 = Cl, R2 = H) and the chloro aldehyde (107 R1 = Cl, R2 = CHO). 

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... 

Metallation of benz- and dibenz-azepines has been little investigated. 10,11-Dihydro-5 f/-dibenz[6,/]azepine lithiates at the 4-position, this being a convenient route to the 4-carboxylic acid (74CRV101). 

With the exception of the photosensitized reaction of methyl acrylate with 1-benzoylindole to produce the four-membered ring adduct, with subsequent conversion into a benz[6]azepine, no other photoinduced cycloaddition reactions of indoles with alkenes have been reported (80 3403). 

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