5//-Dibenz azepines

The only known example of this type of cyclization is the synthesis of dibenz[, /]azepines 457 from appropriate salicylaldehyde 454 and 2,4, 6-trinitrotoluene (455) via the corresponding intermediate 456 (Scheme 72) (62M766). 

Similar problems arise with the four isomeric dibenzazepines 4-7. since only 5//-dibenz-[6,d]azepine (4) and 5//-dibenz[/>,./]azepine (7) can be drawn as fully benzenoid ring structures. Even so, 5//-dibenz[/ ,t/]azepines are rare and are known only as the 7-oxo derivatives.4 In contrast, 5//-dibenz[6,e azepine (5) and 6//-dibenz[r,t>]azepine (6) exist only as the 11//- 5a and 5H- 6a isomers, respectively. In fact, there is no chemical or spectrosopic evidence for the isomerization of 5//-dibenz[e,e]azepine,5 or its 6-oxide,6 to the 6//-dibenz[r, e]azcpinc isomer (6). In addition, an X-ray crystal structure of 7-methoxy-5//-dibenz[e,e]azepine supports unequivocally the benzenoid rather than the quinonoid form.7 9//-Tribenz[6,d /]azepine (8) has only recently been prepared.8... 

Surprisingly, X-ray structural analysis of the dark-green, hygroscopic tetrabutylam-monium salt of 5//-dibenz[6,/]azepine reveals that the potentially antiaromatic 5//-dibenz-azepine anion has a less pronounced nonplanar butterfly structure (161° vs. 144 ) than 5H-dibenz[6,/]azepine.243... 

In accord with experimental observations, SCFMO calculations indicate that an /V-acyl function should deactivate 5f/-dibenz[/>,/]azepine towards electrophilic substitution at the carbocyclic rings, and that substitution should occur preferentially at the CIO position.32 The calculated dipole moment (0.98 D) for 5f/-dibenz[A,/]azepine compares favorably with the measured value (0.96 D), and is expected for a nonplanar ring system.58... 

The pharmacologically active and commercially important 5//-dibenz[/>,/]azepines 40 are available by base-catalyzed dehydrobromination of their 5-acyl- 10-bromo-l 0.11-dihydro derivatives 38,118 followed by hydrolysis of the isolable tV-acyl compounds 39 29.119-121... 

On prolonged treatment in refluxing 5% aqueous ethanolic sodium hydroxide, 5-acetyl-ll-fluoro-10-(pentafluoroethoxy)-10,l l-dihydro-5f/-dibenz[/>,/]azepine (53) 30 undergoes dehy-drofluorination and deacetylation to give 10-(pentafluoroethoxy)-57/-dibenz[Z>,/]azepine (54) in 92% yield.135... 

Saponification of the a,/ -unsaturated ester 59, prepared by a Reforma tsky reaction on 8-chloro-5-methyl-5//-dibenz[/>,/]azepin-10(ll//)-one, is accompanied by migration of the exocyclic C —C double bond to form the 5W-dibenz[/>,/]azepine 60.72... 

In hot polyphosphoric acid (PPA), 1-arylindoles undergo ring expansion to 5//-dibenz[/>,/]-azepines 14 in modest yields (8 65%).239... 

Mcthyl-5//-dibenz[/>,/ azepinc 5-oxidc (3) is deoxygenatcd rapidly and in high yield to 5-methyl-5//-dibenz[/>,/]azepine (4) by aqueous sodium sulfite, and, less efficiently and accompanied by deniethylation, by heating at 160-170 C for 20 minutes.124... 

Electrochemical reduction of 5-acetyl-10-bromo-5/f-dibenz[ >,/]azepine in the presence of quinoxalinc as a moderator and diethyl malonate as a proton donor, effects rapid and quantitative hydrodebromination without loss of the acetyl group.183... 

Acid-catalyzed aminomethylations of 5W-dibenz[/>,/]azepine (5) in ethanolic solution with formaldehyde and a secondary amine yield the 2-(aminoalkyl) derivatives, e.g. 6.186 If acetic acid is used as the solvent, however, then 2,8-bis(aminoaIkylatiou), e.g. formation of 7, results. 

Attempts to prepare 5-vinyl-5F7-dibenz[b,/]azepine by alkylation of 5i/-dibenz[b,/]azepine with 2-chloroethyl-p-toluenesulfonate followed by dehydrochlorination, or by direct vinylation with acetylene under pressure in toluene or in dimethyl sulfoxide, have failed.194 Also, 5H-dibenz[b,/]azepine fails to react with acryloyl chloride, although the 5-acryloyl derivative 8 (R = COCH = CH2 mp 122 — 123 C) has been prepared in 65% yield by condensing dibenz-azepine 5 with 3-chloroacryloyl chloride, followed by dehydrochlorination of the product with l,8-diazabicyclo[5.4.0]undec-7-ene in dimethyl sulfoxide at 80-90°C.194... 

Bis(bromomethyl)-5//-dibenz[/), / ]azepines, e.g. 12, prepared by free-radical bromination of the 10,11-dimethyl compound with yV-bromosuccinimide, on treatment with a primary alkyl-amine followed by alkaline hydrolysis, yield l,2,3,8-tetrahydrodibenzo[. /]pyrrolo[3,4-<7]-azepines, e.g. 13, which possess useful pharmacological properties.91,163... 

The heteroaryne 15. produced by treating 5-aeetyI-10-bromo-5//-dibenz[/>,/]azepine (14) with potassium rm-butoxide (see Section 3.2.1.4.2.), has been trapped by cyclohexa-1,3-diene8 and by furan118 as the [4 + 2] cycloadducts 16 and 17, respectively (see also Section 3.2.1.1.1.1.).118... 

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.). 

Low yields of the 5-acetyl-l0,11-epoxy derivative 11 (R = Me) are also obtained by oxidation of 5-acetyl-5//-dibenz[/>,/]azepine (10, R = Me) with iodoxybenzene and vanadium(lll) acetylacetonate, and with iodosobenzene and iron(lll) porphyrin.220... 

Dihydroacridine-10-carbaldehyde (4) is the major product (57%) from the oxidation of 1 l//-dibenz[7),e]azepine (3) with peracetic acid.222 1 l//-Dibenz[/),e,]azcpin-6(5/7)-one (5) is also formed along with trace amounts ( < 4 %) of 9-acridone-10-carbaldehydeand 5,6-dihydro-l 1H-dibenz[ >,< ]azepine-6,l 1-dionc. 

Dialkyl-5//-dibenz[/>,/]azepines 6 on oxidation with 3-chloroperoxybenzoic acid undergo ring contraction to 9,10-dihydroacridinc-9-carbaldehydes 7.223 In contrast, 5,10,11-trialkyl derivatives 8 yield mixtures of the acridinyl ketones 9 and 10,11-epoxides 10. 

Acetyl-5//-dibenz[/>,/]azepine-10-car bon itrile (17, R = CN) when treated with sodium borohydride undergoes reduction (73 % yield) at the CIO - Cl 1 double bond without reduction of the acetyl or cyano groups.212 However, hydroboration of 5-acetyl-5//-dibenz[/y/]azepine (17, R = H) with diborane in tetrahydrofuran under standard conditions is accompanied by reduction of the acyl function to yield 5-ethyi-10,l l-dihydrodibenz[6,/]azepin-10-ol (18).72... 

Reductions of 5-substituted 10-nitro-5//-dibenz[/ ,/]azepines 19 (R = CN, CONH2) with various reducing agents have been studied in detail. The major products 20 and 21 are summarized in the reaction schemes below.185... 

Nitroso-5//-dibenz[/j,/ azepine (see Section 3.2.1.5.4.1.) in methanolic hydrochloric acid undergoes rearrangement and ring contraction to a mixture of acridine (59%), acridine-9-carbaldehyde (trace), and 2-nitro-5//-dibenz[/ ,/ azepine (3% mp 176-178 C).184 However, in acetone and hydrochloric acid, the aldehyde (57 %) becomes the major product. On thermolysis, (or photolysis in the presence of oxygen), in hydroxylic solvents, the nitroso compound yields mainly acridine (36-76%) together with minor amounts of either 2-nitrodibenzazepine (4-6% by thermolysis) or acridine-9-carbaldehyde (18% by photolysis). However, in non-hydroxylic solvents, e.g. cumene, acridine-9-carbaldehyde (64%) is the major product. 

F-Dibenz[/),/]azepines enter into 1,3-dipolar cycloadditions with diarylnitrilimines 14, generated in situ from hydrazonyl chlorides, to give dibenzo[7>,/]pyrazolo[3,4-rf]azepines, e.g. 15, in good yields.233... 

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). 

Only a few polar additions to azepines have been reported of which the most common are the electrophilic additions to the 10,11-bond of 5//-dibenz[ >,/]azepine these have been reviewed (74CRV101). The N-acetyl derivative adds fluoroxypentafluoroethane and the adduct on treatment with sodium hydroxide eliminates HF to yield lV-acetyl-10-perfluoroethoxy-5//-dibenz[6,/]azepine (80JOC4122). 

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). 

Marked differences in the UV spectra of 1-alkyl- and l-acyl-dibenz[ >,/] azepines support the view that the TV-acyl derivatives are best described as the polar canonical dibenz-azepinium mesomers (32), in which the nitrogen lone pair is delocalized onto the oxygen,... 

Reduction of 5/T-dibenz[ >,/]azepine with sodium borohydride in acetic acid yields the lV-ethyl-10,11-dihydro derivative (124 R1 = Et, R2 = H), reduction of the double bond being accompanied by reduction of the N-acetyl group formed in situ (74JA7812). In contrast, sodium borohydride in methanol reduces 5-acetyl-10-cyanodibenz[6,/]azepine to the 5-acetyl-10,11-dihydro derivative (124 R1 = Ac, R = CN) (76T1345). 

Furthermore, in the addition of bromine to 44 (in 1,2-dichloroethane, chloroform or carbon tetrachloride, see Scheme 19) to obtain the trans dibromo derivative99 (47), which is found to be in two main conformers100, the formation of the bromonium ion (46) from 5//-dibenz[ >,/]azepine-5-carbonyl chloride (44) is a reversible step. The formation of the bromonium ion (46) follows the association of reagents in the CT complex (45). 49 reacts with hydrogen bromide through the protonated 48, forming" both the dibromo derivative 47 and the olefin 44. The bromonium ion (46) is the probable intermediate... 

As the prototypical amide-containing compound, carbamazepine (5H-dibenz [ >,/]azepine-5-carboxamide) ... 

We have introduced the concept of homoheteroaromaticity (the equivalent of homoaromaticity [18] for heterocycles) to describe the structure of some cations obtained by protonation of l//-azepine (4) and 5//-dibenz[/ ,/]azepine (5). B3LYP/6-311++G, GIAO, and NICS calculations together with some NMR experiments lead us to conclude that the neutral molecules are antiaromatic and that the cations 6 and 7 are homoaromatic [22],... 

Azepines are frequently the products of ring transformation reactions. Thus 1-arylindoles have been converted into 57/-dibenz[/ /]azepines in an unusual acid-catalysed rearrangement <95T2091> and a number of 3-acyl-4-(indol-3-yl)-2-methyl-4,5-dihydro-l//- 1-benzazepines have... 

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