57/-Dibenz azepin-10-ones

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... 

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. 

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). 

H-Dibenz[6,eJazepin-6-one, 11-hydroxy-ring contraction, 7, 516 11H-Dibenz[6,ejazepin-1 l-one, 6-phenyl-synthesis, 7, 532 Dibenz[6,/]azepin-2-one synthesis, 7, 525... 

One gram of 6,7-dihydro-5H-dibenz[c,e] azepine hydrochloride was dissolved in water, made alkaline with concentrated ammonia, and the resultant base extracted twice with benzene. The benzene layers were combined, dried with anhydrous potassium carbonate, and mixed with 0.261 g of allyl bromide at 25°-30°C. The reaction solution became turbid within a few minutes and showed a considerable crystalline deposit after standing 3 A days. The mixture was warmed VA hours on the steam bath in a loosely-stoppered flask, then cooled and filtered. The filtrate was washed twice with water and the benzene layer evaporated at diminished pressure. The liquid residue was dissolved in alcohol, shaken with charcoal and filtered. Addition to the filtrate of 0.3 gram of 85% phosphoric acid in alcohol gave a clear solution which, when seeded and rubbed, yielded 6-allyl-6,7-dihydro-5H-dlbenz[c,e] azepine phosphate, MP about 211°-215°C with decomposition. 

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... 

Detailed IR and UV spectroscopic data on 5//-dibenzfc,c]azepine5 and its 7-methoxy- and 7-methylsulfanyl derivatives7 have been reported. IR, UV and HNMR spectroscopic data for 2-amino-3//-l-benzazepin-3-one, 2-amino-l//-3-benzazepin-l-one, and 6-amino-7H-dibenz[7>,(/]azepin-7-one have been gathered,27 and confirm their oxo amidinc structures. Spec-trophotometrically determined pATa values of 4.46 and 5.20 (in water at 21 C) have been obtained for 1 l//-dibenz[(>,e]azepine and its 6-methyl derivative, respectively.28... 

Molecular orbital based molecular mechanical (MOMM) calculations have been carried out on 3H-2-benzazepinyl phosphonates.43 Similar calculations on 5//-dibenz[Z>,/]azepine lead to the prediction that there are two stable boat conformations for the seven-membered ring both of which are more stable than the planar form by 22.6 and 10.9 kJ moP, respectively the more stable conformer being the one in which the proton on nitrogen is exo lo the azepine... 

Bromo-6-ethoxy-7//-dibenz[/>,d]azepin-7-one(28, R1 = OEt Rz = Br). prepared by oxidation of the 5,6-dihydro derivative 27 with manganese(IV) oxide, is one of the few examples of unsaturated dibenz[/>,d]azepines to be reported.4 Earlier reports concerning the preparation of the parent system 28 (R = R2 = H) are incorrect the product is in fact a dimer.115... 

Hydrolyis of the enamine 34, formed by addition of (2-fluorophenyl)lithium to 9-chloro-6-vinyl-5//-dibenz[c,c]azepin-7(6//)-one (33) at — 70 C, yields the 57/-dibenz[c,e]-azepine 35 as the ... 

Reduction of 2/f-dibenz[/i,/]azepin-2-one (55) with aqueous sodium dithionite (Na2S204) yields 5tf-dibenz[6,/]azepin-2-ol (56), which, in the presence of oxygen and a strong base, undergoes retrooxidation to the dibenzazepinone 55.13h... 

Dibenz[r,e,]azcpinium salts, e.g. 3 and 6, arc also obtained by O- and 5-alkylation of 6,7-dihydro-5//-dibenz[f,e]azepin-7-ones 2 and -7-thiones 5 with trimethyloxonium tetrafluo-roborate.181 iodomethane,181 or methyl trifluoromethanesulfonate.12 Treatment of the tri-fluoromethanesulfonates 3 and 6 (X = OTf), or the tetrafluoroborate 6 (X = BF4) with 2 M sodium hydroxide in dichloromethane liberates the free bases 4 and 7, respectively.7,181... 

Friedel-Crafts acylation of 5-acyl-56/-dibenz[6,/]azepines, e.g. 3, affords the 5,10-diacyl derivatives, e.g. 4.32 Curiously, 5-methyl-5//-dibenz[6,/]azepine is unreactive towards electrophilic acylation and only trace amounts of a product, identified tentatively as 2,8-diacetyl-5// dibenz[6,/]azepin-10-one, have been isolated. 

Direct conversion of the 5/7-dibenz[i,/ ]azepin-10(l 177)-one 45 to the lO-(alkylsulfanyl) derivatives 46 has been achieved using an alkanethiol and aluminum trichloride.21-1... 

Fluorodehydroxylation of 5-benzyl-5//-dibenz[f>,/]azepin-10(lli/)-one (47) with hydrogen fluoride and sulfur tetrafluoride followed by catalytic debenzylation of the product 48 provides access to 10-fluoro-5//-dibenz[ft,/]azepine (49).134... 

Amino-77/-dibenz[/),t/]azepin-7-ones, e.g. 7, prepared either by successive bromination, aminodebromination, and dehydrogenation of 5-tosyl-5A/-dihydro 7>,t/]azepin-7(6//)-ones, or by the oxidation of 6-ethoxy-6,7-dihydro-5//-dibenz 7>,r/]azepincs with lead(IV) acetate followed by aminodemethoxylation, on treatment with a bidentate nucleophile (e.g.. benzene-1,2-diamine or 2-aminobenzenethiol) yield the pentacyclic systems 8 and 9, respectively.27... 

Oxidation of 5//-dibenz[7>,/]azepine (12) with Fremy s salt [ON(S03K)2] yields a mixture of acridine-9-carbaldehyde (13) and 2//-dibenz[A,/]azepin-2-one (14).215 The dibenzazepin-2-one 14 is also obtained in 46% yield with bis(trifluoroacetoxy)pentafluoroiodobenzene [PhI(OCOCF3)2] in acetonitrile as the oxidant.221... 

Acridine-9-carbaldehyde (24%) is one of several products formed from the oxidation of 5//-dibenz[A/]azepine with tert-butyl hypochlorite in dichloromethane at — 70 C.229 The reaction is even more complex in the presence of silver(I) trifluoroacetate, and an analysis of the reaction mixture by GC-MS techniques reveals the presence of eleven products, the major ones being acridine (37%), an unidentified 5//-dibenz[/ ,/]azepinecarbaldehyde (23%) and acridine-9-carbaldehyde (9 %). 

CN ( )-r-[3-(3-chloro-10,l I-dihydro-5//-dibenz[6/ azepin-5-yI)propyl]hexahydrospiro[imidazo[l,2-a]pyridine-3(2//),4 - piperidin]-2-one... 

Desipramine Desipramine, 10,1 l-dihydro-5-[3-(methylamino)propyl]-5H-dibenz[b,f] azepine (7.1.13), differs from imipramine in that it contains only one methyl group on the nitrogen atom of the propylamine side chain. The suggested methods of desipramine synthesis are very simple, and the difference lies only in the manner in which the secondary methylamine group is introduced into the structure of the drug. 

Considerable interest has been shown in dibenz[c,e]azepines as examples of optically active 2,2-bridged biphenyls (68MI51600). The absolute configurations of some dibenz[c,e]azepines have been determined (b-77SH(2)305), and the CD spectra of the hydro-2-benzazepin-l-one (22) recorded (78CHE538). In contrast, to analogous five- and six-membered lactams, azepinone (22) has a (+) Cotton effect. 

Some difficulty has been encountered with the TV-alkylation (e.g. with ethyl bromoacetate) of 2,3,4,5-tetrahydro-l//-l-benzazepin-5-one (31 R = H) (74JCS(P1)1828). The pharmacological activity (Section 5.16.5) of TV-substituted 5H-dibenz[6,/]azepine and its 10,11-dihydro derivatives has resulted in an intensive study of the TV-alkylation of these ring systems (74CRV101). Generally, alkylation is effected with an alkyl halide or tosylate in the presence of base. Phase transfer TV-alkylations of 5H- dibenz[6,/]azepine have been reported. The method, however, is less successful with the 10,11-dihydro derivatives (79MI51600). 

O -Alkylations of azepin-2-ones, and benzazepin-2-ones, are most efficiently brought about by trialkyloxonium tetrafluoroborates (Meerwein s reagents) (B-69MI51600,73JOC1090, 81HCA373). S-Alkylation of the thiones is effected similarly. These oxonium salts have also proved useful for the alkylation of azepinedione precursors of azatropones and azatropolones (72JOC208) (see also Section 5.16.3.1.2). 5//-Dibenz[f>,e]azepine-6,11 -dione with triethyloxonium tetrafluoroborate O-ethylates at the amide carbonyl and not at the ketonic carbonyl as was first proposed (72AJC2421). 

Alkylation of 3-methyl-1,2,4,5-tetrahydro-3//-3-benzazepin-2-one in THF-DMF solution containing sodium hydride, with primary and secondary alkyl halides and with a-bromoesters, results predominantly in 1-monoalkyl derivatives, whereas with w,w-dibromoalkanes, 1,1-spiro derivatives are formed (80T1017). Apparently, 6,7-dihydro-5//-dibenz[6,rf]azepin-6-one does not condense with benzaldehyde or with nitrosobenzene at the active methylene group (55JA3393). 

Oxidation of 5//-dibenz[6,/]azepines by Fremy s salt has been examined closely. At pH 7.5 the quinonoid dibenz[6,/]azepin-2-one is produced together with acridine-9-aldehyde (74CRV101). 3-Chloro-10,11 -dihydro-5//-dibenz[6,/]azepine yields a mixture of the quinoneimines (174 R=C1) and (175) which with sodium dithionite reduce to the corresponding chlorohydroxydihydrodibenzazepines (76JHC269). 

Oxidation of 1 l//-dibenz[6,< ]azepine with peracetic acid yields the dibenzazepin-6-one and N-formylacridan as the major products. Both products most probably result from an oxaziridine intermediate (76JCS(Pi)l29l). 

The reduction of dibenz[6,e]azepine-5,ll-dione has been studied intensively (65CCC445). Clemmensen reduction, or reduction over palladium in acetic acid, yields the -ll//-5-one, whereas reduction over Adams catalyst furnishes the ll-hydroxy-5-one. Sodium in butanol effects reduction to a mixture of the -ll//-5-one and its 7,8,9,10-tetrahydro derivative. 

Preparative routes to 5/7-dibenz[6,e]azepine-6,11 -diones (morphanthridinediones) are based mainly on the cyclization of 2-aminobenzophenone-2 -carboxylic acids and their derivatives (55LA(594)89). Studies on a-aminodiphenyImethane-2 -carboxylic acid reveal that cyclization to 5,11 -dibenz[6,e ]azepinone (188) is much slower at room temperature than the cyclizations of the analogous 2-aminobiphenyl-2 -carboxylic acid and the 2 -aminobiphenylacetic acid (189), which at room temperature cyclize spontaneously to phenanthridone and dibenz[f>,d]azepin-6-one (190) respectively (61JOC1329). The hydrogen bromide-induced cyclization of dinitriles (Scheme 16) is adaptable to the synthesis of 2-amino-7-bromo-3//-azepines and 5H-dibenz[c,e]azepin-7-ones (67JOC3325). Apparently, for unsymmetrical dinitriles cyclization is such as always to give the azepine with the bromo substituent attached to the carbon of the a,j8-unsaturated nitrile as exemplified in Scheme 16. 

The acid-catalyzed ring expansions of tertiary cyclohexylazides to tetrahydroazepines may be viewed as an intramolecular version of the Schmidt reaction and in general proceed in high yield. Unfortunately, the reaction is of little synthetic value as the imines formed are readily hydrolyzed to w-aminoketones in the strong acid media (B-67MI51600). However, the reaction is successful with 9-azido-9-phenylacridone, which on thermolysis or photolysis ring-expands to a mixture of 9-phenyliminoacridone (15-35%) and 6-phenyl-11//-dibenz[6,e]azepin-ll-one (65-85%) (76TL3141). 

---