Benzo azepines

Cyclocondensation of 2-iminopiperidine hydrochloride with an E-Z isomeric mixture of ethyl 2-cyano-3-methylsulfanyl-3-(l,2,4,5-tetrahydro-3//-benzo[ azepin-3-yl)acrylaLc in DMF in the presence of DBU at 100 °C gave 2-substituted 6,7,8,9-tetrahydro-4f/-pyrido[l,2-u]pyrimidine-3-carbo-nitrile (01EUP1074549). 

Michael adducts 58 and 2-ethoxy-3,4-bis(methoxycarbonyl-3//-benzo-djazepine (59). The latter product was obtained in 20% yield. 2-Ethoxy-1-methyl-1//-indole (57, R = CH3) yielded exclusively the corresponding 1//-benzo[ ]azepine (60), in a much higher yield (72%). The (2 + 2)-cycloadduct (61) was proposed to be the unstable intermediate in both reactions. 1,3-Dimethyl-1//-indole (62a) was reported to react with dimethyl acetylenedicarboxylate only in the presence of boron trifluoride diethyl etherate as a catalyst.65 In the reaction mixture, two isomeric Michael adducts and a thermally unstable product were... 

The reaction takes place via C-C insertion and leads to novel benzoazepines such as ethyl 177-benzo[fc]azepine-l-carboxylate and ethyl 3/7-benzo[ /]azepine-3-carboxylate, in excellent yields with a high degree of selectivity. Similar results were observed using 10 mol % of Rh2(OAc)4. It is noteworthy that no reaction was... 

Among azepines and their benzo derivatives, antiaromatic IH-azepine 14a is known as a very unstable (even at -78°C in CDCI3 solution) red oil which in the presence of acid or base rearranges to the marginally... 

Ethoxy-3//-azepin-3-ones, e.g. 2, are produced rapidly (2-20 min), as yellow gums, by the oxidation of 7-ethoxy-6-hydroxy-4/T-azepines,e.g. 1, with2,3-dichloro-5,6-dicyano-l,4-benzo-quinone (DDQ) in benzene.48,51... 

In contrast to 6-azidobenzo[/)]thiophene, which yields only benzo[i]thiophen-6-amine (9 %) and JVh,Ar(1-diethylbenzo[/)]thiopheiie-6,7-diamine (25 % bp 175-177 C/0.7 Torr), 6-azido-2,3-dibromobcnzojhjthiophene (1 a, R = R2 = Br) on irradiation in diethylamine in the presence of pyrene, a triplet nitrene quenching agent, yields a mixture of 2,3-dibromo-./V6,./V6-diethyl-benzo[5]thiophene-6,7-diamine (2a, R1 = R2 = Br 13%) and the 8W-thieno[2,3-r]azepine 3a.14<1 Likewise, methyl 6-azidobenzo[6]thiophene-2-carboxylate (lb, R1 = C02Me R2 = H) yields the thienoazepine ester 3b.147... 

A-Silylaldimine condensation with the lithiated intermediate 16 (Scheme 6), after working up the reaction under acidic conditions, produced an amino alcohol that can then be dehydrated to the benzo[d]azepine system 17 (R = Ph) <00JHC1061>. 

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused l-azabicyclo[m.n.O]alkanes, the perhydrobenzo[/]pyrrolo[l,2-a] azepine 29 was prepared in 72% yield . 

The special case of the fusion of a five-membered ring to the benzoheteropine ring occurs when the pyrrole or indole N1 and C2 atoms serve as fusion sites (Figure 2). The resultant benzopyrrolo[l,2-fl]azepines differ by the position of the fused benzo ring and are listed in the order of benzo[c]pyrrolo[l,2-fl]- (7), benzo[d]pyrrolo[l,2-fl]- (8), benzo[e]pyrrolo[l,2-fl]- (9) and benzo[/]pyrrolo[l,2-fl]-(10) azepines, respectively. 

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... 

Intramolecular electrophilic reactions of substituted pyrrole-2-carboxylic acids or their amides lead to benzo[d]pyrrolo[l,2-a]azepinones. Acid 70 in this fashion undergoes Fiiedel-Crafts cyclization to furnish fused azepine 71 in good yield (Equation (6) (2000JOC2479)). 

Several azepine ring constructions have been reported using palladium catalyzed C-C bond formation. Palladium catalyzed cyclizations of substituted tryptamine derivatives 73 lead to benzo[d]pyrrolo[l,2-a]azepinones 74 (Equation (8) (2000JMC1050)). 

Tetracyclic benzo[/]-4-oxopyrrolo[l,2-fl]thieno[3,2-c]azepine 103a, as well as its piperidone homolog 103b, can be prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams 102 (Scheme 20 (2001 HI 519)). 

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)). 

Contrary to the stable azepines and diazepines, benzo[ 7]benzofuro[2,3-/][l,4]-oxazepine 272 undergoes ring cleavage under reductive conditions in the acetic acid/acetic anhydride to afford open chain acetoxy amine 273 (Scheme 58, Section 3.2.2 (2001JHC383)). 

Semiempirical and molecular mechanics calculations have been widely used. Thus, conformation of indolo benzazepine 423 (Figure 8) with its conjugated benzo and indole rings has been studied by molecular mechanics (MMX force field). Its planarity was estimated from a calculation of dihedral angle Ti 2 3 4 the value of ca. 22° is due to strain as contributed by azepine ring. This characteristic was further compared to that of the open-chain and six-membered... 

This review is based on Mosby s book cited above and covers the literature through 2009 together with several articles published in 2010. It includes pyrido[l,2-fl]azepines and their hydro products as well as linearly or angularly fused benzo and dibenzo derivatives. Patents are taken into account provided they reveal important aspects of synthesis or application. 

The nomenclature is not quite uniformly used in the literature. According to Chemical Abstracts, perhydro compound 2 is decahydropyr-ido[l,2-a]azepine, but its oxo derivative 3 (Scheme 2), for instance, is named octahydropyrido[l,2-a]azepine-8(2H)-one. Examples of benzo-fused parent systems frequently dealt with in the following sections can also be found in Scheme 2 (98MI2 cf. Section 2.9.1) ... 

Benzofurazans are thermally more stable but can be cleaved photolytically. For example, benzo-furazan itself in benzene affords cyanoisocyanate (17) and azepine (18), the latter being formed by reaction of the solvent with the putative intermediate acylnitrene (19) (Scheme 5) further supporting evidence for the proposed pathway is provided by trapping the nitrile oxide precursor with dimethyl acetylenedicarboxylate and isolation of the methylurethane derivative of the isocyanate <75JOC2880>. Photolysis of diphenylfurazan yields benzonitrile, diphenylfuroxan and 3,5-diphenyl-1,2,4-oxadiazole. 

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