Azepin-3-ones, 1,2-dihydro

H-Azepinium perchlorate, 6,7-dihydro-formation, 7, 512 Azepinoindoles synthesis, 7, 537 Azepin-2-one, hexahydro-chlorination, 7, 517 synthesis, 7, 530 Azepin-2-one, 3-hydroxy-methylation, 7, 518... 

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. 

A suspension of 100 g of 7-chloro-6-phenyl-1-methyi-3-hydroxy-1,3-dihydro-2H-1,4-benzodi-azepin-2-one in 700 ml of anhydrous pyridine, kept stirred between 0°C and -t5°C, is slowly treated, during 20 to 30 minutes, with 54.5 ml phenyl chlorocarbonate. The temperature is gradually allowed to rise to 20°-25°C and stirring Is maintained at this temperature during 24 hours. 

Chemical Name 5-(o-Chlorophenyl)-7-ethyl-1,3-dihydro-1-methyl-1H-thieno[2,3-e] -1,4-di-azepin-2-one... 

Recently, a one-pot conversion of 2-methoxy-2,3-dihydro-3,6-alkanooxepins to imidazoazepine derivatives by treatment with glycine methyl ester was reported. In the heptano series a symmetrical azepine triester was isolated as a byproduct.206... 

Dehydrogenation is a rarely used method for the production of fully unsaturated azepines, and there are no examples of its use for the formation of simple monocyclic systems, although 3-hydroxy- and 3-methoxy-2//-azepin-2-ones can be obtained by dehydrogenation of the corresponding l,5-dihydro-2//-azepin-2-ones with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in benzene in a sealed tube at 100 48-51-52-67... 

Methyl-5-oxo-l-phenyl-4,5-dihydropyrazol-4-ylidene)-2,3-dihydro-l//-azepine (3), formed in 62% yield by the condensation of 2-amino- or 2-butoxy-37/-azepine with 3-methyl-l-phenylpyrazol-5(4//)-one, with Meerwein s reagent yields the tetrafluoroborate salt 4 which, on treatment with sodium dihydrogen phosphate, liberates the free base 5.64... 

A diatropic cation 15 is also noted in strong acid solution for 7//-pyrrolo[l,2-a]azepin-7-one (14), prepared by dehydrogenation of its 5,6-dihydro derivative 13.217 It is presumed that the deep-red solution produced on treating 7-methylene-7//-pyrrolo[l,2- azepine (16), prepared from the ketone 13 as indicated, with strong acid is indicative of the formation of 7-methylpyrrolo[l,2-a]azepinium cation 17 however, the salt could not be isolated nor a satisfactory HNMR spectrum obtained.217... 

On heating, the dichlorooxazolo[3,4- ]azepine 26, for which dimerization is prevented by the chloro groups, undergoes ring contraction and aromatization, involving a [l,2]-chlorine shift, to 5,8-dichloro-l,4-dihydro-2//-3,l-benzoxazin-2-one (27).11,153... 

Chloro-8//-thieno[3,2-c]azepin-8-one (23), which on the basis of its HNMR spectrum appears to exist as the polar mesomer 24, is obtained in 80% yield by treating the 4,5-dihydro-derivative 22 successively with rm-butyl hypochlorite in cold dichloromethane, and triethylamine.19... 

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... 

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... 

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... 

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. 

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... 

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>... 

The ring rearrangement of 8a-(l-hydroxy-alkyl)-hexahydro-oxazolo[3,4- ]pyridin-3-ones 163 upon treatment with sulfuryl chloride was reported in 2004 activation of the alcohol and ring extension produces 5,6-dihydro-l//-oxazolo[3,4-tf]azepin-3-ones 164 in excellent yields (Scheme 48) <2004H(63)17>. 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

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)). 

The second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-17f-l,4-benzodi-azepin-2-one (5.1.1)—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-17/-l,4-benzodiazepine (5.1.41), and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyliodide, using sodium hydride as a base [41,42]. 

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. 

Medium-sized and large ring systems often show complicated conformational interconversions involving pseudorotations in one or even more conformational families. This makes stereochemical assignments in diastereomers rather difficult. Thus, very few systematic studies have been published. The situation is improved if such rings are embedded in polycyclic systems, or if they contain double bonds, which leads to restricted conformational mobility. An example is the differentiation of diastereomeric 2,3-dihydro-lf/-benzo[6]azepines 1 on the basis of y-gauche effects and on d(13C) and 3/H H values640. 

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). 

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). 

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). 

Reports of pericyclic cyloadditions to other azepine systems are rare. Addition to the diene system of 6,7-dihydro-l//-azepines occurs readily with DMAD (72CPB1740) and with N-phenylmaleimide (73JA7320). The 5,5a-dihydro-3-benzazepin-2-one (157), a suspected but non-isolable intermediate in the formation of l,2,4,5-tetrahydro-3//-3-benzazepine-2,4-diones by photoaddition of diphenylketen to amino-2//-azirines, has been trapped in the photolysate by N-phenyl-1,3,4-triazoline-2,4-dione as the [4+2]tt adduct (158). Its structure was confirmed by X-ray analysis (80JOC2951). 

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