Pyrido azepine

Antidepressant heterocycles including mianserin (a dibenzoazepine), mirtazepine (a benzo[pyrido]azepine) and methiothepin (a dibenzothiepine) increase the lifespan of... 

H-Pyrido[3,2-c]azepine, 7-methoxy-nucleophilic displacement reactions, 7, 514 Pyridoazepines synthesis, 7, 535, 540 Pyridoazepinones synthesis, 7, 531 Py rido[2,1-a]benzazepin-6-one physiological properties, 7, 546 Py rido[ 1,2-a]benzimidazoles reactions, 6, 1041... 

Reaction of 3-formyl-2-[A-(2-alkenyl)-A-benzylamino]-4//-pyrido[l, 2-n]-pyrimidin-4-ones 252 and primary amines in the presence of MS (4 A) afforded pyrido[l, 2 l,2]pyrimido[4,5-Z)]azepin-6-ones 253 (96T13081). 

Reaction of 2-(A -alkyl-A -benzylamino)- and 2-[A -(rraM-crotyl)-A -ben-zylamino]-3-formyl-4/7-pyrido[l,2-n]pyrimidin-4-ones (260, R = H, Me) with tosylamine gave compounds 268 via compounds 266 and 267 (96T13097). The results of kinetic studies and MP3 calculations on the 3-formyl derivatives 252, 260 and the imines 262, 263 suggested a concerted nature for azepine-ring formation. 

Cyclocondensation of 2-iminopiperidine hydrochloride with an E Z isomeric mixture of ethyl 2-cyano-3-methylsulfanyl-3-( 1,2,4,5-tetrahydro-3/f-benzo[r/ azepin-3-yl)acrylate in DMF in the presence of DBU at 100°C gave 2-substituted 6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-carbo-nitrile (01EUP1074549). 

Few heteroaryl-substituted 37/-azepines are known however, photolysis of 2-(2-azidophenyl)-pyridine (80) in diethylamine provides Ar,Ar-diethyl-3-(2-pyridyl)-3/f-azepin-2-amine(81), along with minor amounts of pyrido[3,2-6]indole (82) and the mesoionic pyridofl, 2-7>]indazole (83).191... 

Later studies demonstrated that the yields of A-alkyl-5L/-pyrido[2,3-c]azepin-9-amines 7 from 8-azidoquinoline 6 are enhanced by the presence of a 6-methoxy group107 108 and that ring expansion is now possible in secondary aliphatic amine solution. In each case, however, significant yields of quinolinediamines 8 are also produced. 

Azido-6-methoxyquinoline (15) under similar photolysis conditions produces, initially, a separable mixture of the isomeric dimcthoxy-5/7- and dimcthoxy-7//-pyrido[2,3-r azepine 16 and 17.107 However, if the photolysate is left to stand overnight at room temperature before neutralizing with hydrochloric acid, then only the 5//-isomer 16 (76%) is isolated. 

Azido-5-chloroisoquinoline (18) in methoxide/methanol/dioxane solution undergoes ring expansion to the 5//-pyrido[3.4-c]azepine 19 accompanied by its hydrolysis product, the py-ridoazepinone 20. 5//-Pyrido[3,4-c]azepin-9(8//)-one is the main product from the photolysis of 5-azidoisoquinoline under the same conditions.151... 

Methoxy-5//-pyrido[2,3-c]azepin-9(8//)-one (4) on chlorodehydroxylation with phosphoryl chloride in A,A, -dimethylaniline yields a mixture (20 %) of the chlorc)-6-methoxypyrido[2,3-c -azepines5and6.192 An unseparablemixture (3 7) of 5H- and 7ff-pyrido[2,3-c]azcpine-9-thione 7 and 8 is obtained on treating the pyridoazepinone 4 with phosphorus pentasulfide in warm pyridine. 

In contrast, chlorodehydroxylation of the isomeric 9-methoxy-5//-pyrido[3,2-r]azepin-7(6//)-one (9) furnishes, in poor yield, a mixture of the unstable 7-chloro-9-methoxy-5//-pyrido[3,2-c]azcpine (10) and, unexpectedly, the dichloro derivative 11.192... 

Arylation of the azepine ring has been carried out by treating either 9-chloro-6-methoxy-5/7-pyrido[2,3-c]azepine (50, X = Cl) as a mixture with the isomeric 9-chIoro-6-methoxy-7A/-py-rido[2,3-c]azepine (see Section 3.2.1.5.5.1.). or, better, the 6,9-dimethoxy derivative (50, X = OMe) with phenyllithium.152 In the former case, a mixture (20%) of the 9-phenyl-5//-and 9-phenyl-7//-pyrido[2,3-c]azepine is formed. 

Treatment of a mixture of 6-methoxy-9-chloro-7//- and 6-methoxy-9-chloro-5//-pyrido[2,3-c]-azepine (20) (see Section 3.2.1.5.5.1) with 1-acylhydrazines yields 3-substituted 5//-pyrido[2,3-c][l,2,4]triazolo[4,3-a]azepines, e.g. 21.191 Likewise, with sodium azide in dimethyl sulfoxide, the tetrazolo[4,5- ]azepine 22 is formed in good yield. 

The isomerization of 6,9-dimethoxy-7/7-pyrido[2,3-c]azepine (7) to the 5//-tautomer 8, which takes place slowly (12 h) at room temperature, and more quickly in refluxing ethanol,107 is reversible in the presence of potassium amide.108 Further examples have been noted with other pyrido[2,3-c]azepines.108... 

The same group has developed another synthetically useful photochemically induced domino transformation. Irradiation of the enaminecarbaldehydes 5-40a or 5-40b in the presence of acrylic acid ester 5-41a or acrylonitrile 5-41b afforded the quinolizidines 5-45a and 5-45b as well as the pyrido[l,2-a]azepines 5-45c and 5-45d, respectively, with high stereoselectivity [14]. Only very small amounts of the corresponding diastereomers 5-46a-d were detected. 

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then iV-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>. 

In other somewhat related work, the synthesis of pyrano[2,3-c]azepines (and pyrido[2,3-c]azepines has been described. Reaction of hydrazoic with iV-(5,6,7.8-tetrahydro-2,5-dioxo-2W-l-benzopyran-3-yl)benzamide (or 8-hydrazono) derivatives afforded pyrano[2,3-c]azepines, which in turn can be transformed to pyrido[2,3-c]azepines <00H(53)1111>. 

As in the case of the formation of an azepine (Scheme 43), Pro afforded a pyrrolo[l,2-fl]azepine 88, and pipecolinic acid afforded a pyrido[l,2-a]aze-pine 89 (80JHC1593). 

The Chemistry of Pyrido[l,2-a] azepines and Their Hydro Derivatives... 

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. 

To avoid any confusion arising from the pyridoazepine nomenclature (see Section 1.3), the synthetic sections will be denoted according to the respective unsubstituted bicyclic parent moiety ( derivatives of decahydro-pyrido[l,2-fl]azepine, etc.). 

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