Benzazepinone

Benzazepin-4-one, 2-dialkylamino-hydrolysis, 7, 510 Benzazepinones azatropolone character, 7, 503 synthesis, 7, 529 Benzazepinones, 2-ethoxy-azatropolone character, 7, 503 Benzazepinones, hydroreactivity, 7, 503 Benzazepin-2-ones alkylation, 7, 514 tautomerism, 7, 503... 

Quinolin-2-one, 3-cyano-4-hydroxy-synthesis, 2, 428 Quinolin-2-one, 3,4-dialkyl-Knorr synthesis, 2, 425 Quinolin-2-one, dihydro-Camps synthesis, 2, 418 synthesis, 2, 402 from benzazepinones, 2, 506 from indanone oxime, 2, 487 from indanones, 2, 488 by intramolecular Friedel-Crafts reactions, 2, 421... 

Also noteworthy is the condensation of dimethyl phthalate (71) with TV.A-bis methoxycar-bonyl)alkyl- and -aryl]amines to give 3F/-3-benzazepines which exist as the intramolecularly hydrogen-bonded enol forms, e.g. 72, rather than the generally more stable benzazepinone tautomers.14... 

Chloro-l//-l-benzazepines 2 are obtained as unstable red oils in excellent yields by heating 1 //-l-benzazepin-2(3//)-ones 1 with phosphoryl chloride in pyridine.208 Reaction conditions are important since in the absence of pyridine, or in dichloromethane solution, only poor yields of dimers, e.g. 3, are produced. The chlorobcnzazepines are stable for only short periods (24 hours in anhydrous pyridine) and rapidly polymerize. Isolation of the pure chloro compounds is difficult since they undergo very rapid hydrolysis to the benzazepinones. 

As expected, benzazepines bearing an alkoxy group on the inline carbon center exhibit imidate character and undergo rapid hydrolysis to benzazepinones.80... 

Likewise, amine functions on the azepine ring at an unsaturated carbon center behave as enamines and undergo hydrolysis under both acid and alkaline conditions to the benzazepinones.15,64 8084 However, hydrolysis of dimethyl l-acetyl-5-piperidino-l//-l-benz-azepine-3,4-dicarboxylate(18) yields not the benzazepinone but the tautomeric 5-hydroxy derivative 19.13 Presumably, the enol form is stabilized by intramolecular hydrogen bonding. 

Benzazepin-2-amines can be obtained by nucleophilic displacement reactions on a variety of substrates. For example, the benzazepin-2-amine 22 is formed by treating the thiolactam 21, obtained from the benzazepinone 20 with phosphorus pentasulfide in pyridine or triethylamine solution, with ammonia.61... 

Condensation of l-aryl-8-chloro-4-[(dimethylamino)methylene]-2-3//-benzazepin-5-one5, prepared from the benzazepinone 4 as indicated, with bidentate nucleophiles yields directly the pyrimido[5,4-c/][2]benzazepines 6.217... 

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). This approach is illustrated by the preparation of 1,2,3,4-tetrahydroisoquinolin-l-ones in Scheme 146,86 and examples of applications in benzazepinone synthesis are given later (see Scheme 173 in Section VI,B). 

The effect of variation in the N-l side-chain of (26) on activity was also examined [52]. In the benzazepinone series (26, n = 2), no loss of activity occurred on extension of the side-chain from acetic acid (m = 1) to propanoic acid (m = 2). The butanoic acid homologue (m = 3) resulted in only a slight decrease in activity, whereas the next higher homologue (m = 4) became 1000-fold less active. These results imply unexpected degrees of freedom at the carboxyl binding site. 

Some optically active compounds have been studied [54], The benzazepinone diacid (CGS 12831, 27) was found to have the best in vitro inhibitor potency in a series of lactam compounds, but it showed only marginal biological activity following oral administration, presumably because of poor absorption. The corresponding monoethyl ester (CGS 14824A, 28) was much more potent in vivo [54, 56]. This compound (28) was found to produce dose-dependent antihypertensive effects in conscious normotensive and spontaneous hypertensive rats, generally similar to those produced by enalapril. Evaluation of (28) in healthy volunteers [57, 58] shows that it is an effective,... 

Methyl 2,3-butadienoate can undergo 1,3-dipolar cycloaddition with nitrones leading to the formation of 528, which would undergo homolytic cleavage of the N-O bond followed by radical rearrangement and coupling to afford benzazepinone 531 [239]. 

Several condensed 6-7 bicyclic systems have been prepared from AAs. Some Af -chloroacetylated AAs are photochemically transformed into heterocycles with a condensed seven-membered ring. For example, A-chloro-acetyl-D,L-w-tyrosine is easily cyclized into benzazepinone 109a on irradiation with a high-pressure mercury lamp (67JA1039 68JA776). 

A-(2-Hydroxybenzoyl)-AA, prepared from salicylaldehyde and an AA, when reduced and cyclized with TFAA, afforded l,3-oxazolo[2,3-h][l,3]be-nzoxazinones 128 as a new heterocyclic system [93H(36)2811]. In another group of AAs, the methyl group is transformed into a methylene group to give a benzazepinone derivative. From Met ester the cis and trans isomers of compound 129 were obtained in a 48 52 ratio (92CB2467). 

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... 

Reaction of indolo benzazepinone 27 with phosphorus pentasulfide yields 91% of the corresponding thione 415 (Scheme 87 (1993LA1141)). 

The synthesis of the benzazepinone portion of benazepril began with monobromination of 1-tetralone (35), followed by oxime formation to give 36 (Scheme 10.9). A Beckmann rearrangement mediated by polyphosphoric acid provided the ring-expanded lactam 37. Displacement of the a-bromine with potassium phthalimide installed the necessary... 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

The formation of 3-benzazepinones from /3-(phenethyl)glycine chlorides is also temperature sensitive. Early efforts using aluminum chloride or PPA as catalyst produced mainly tetrahydroquinolones as the major products along with only trace amounts of benzazepinones. Eventually, it was found that the amount of catalyst is critical in determining the size of the heterocyclic ring produced, and that for benzazepine formation an optimum temperature of -10 °C is necessary. 

Dieckmann cyclizations of diesters of type (210) are catalyzed by potassium f-butoxide in toluene, sodium in xylene, or sodium hydride in DMF, and produce 1-benzazepinones in good yields. The method is also applicable to the synthesis of azepines fused to other heterocycles, e.g. pyrrolo[2,3-6]azepin-4-ones (211) (81H(16)399). 

A recent development in the synthesis of 3//-3-benzazepin-2-ones has been the photocyc-lization of A-(chloroacetyl)phenethylamines (Scheme 25). Ring closure is by homolysis of the alkyl halide followed by intramolecular coupling of the alkyl radical with an aromatic radical cation. Yields are good, especially with a stabilizing electron-donating group (MeO, NMe2) at the position meta to the ethylamino function (i.e. ortho or para to the site of cyclization). Isomeric benzazepinones are normally obtained (Scheme 25) with meta-substituted phenethylamines (80H(14)ll). 

The ring expansions of quinolines (74JCS(Pl)1828), 1,2-dihydroisoquinolines (80JOC1950) and 1,2-dihydroisoquinolones (80RTC271) by use of dihalocarbenes have some merit for the synthesis of 1- and 2-benzazepines and benzazepinones. However, the report that 1-phenyl-2,3,4-trioxotetrahydroquinoline on treatment with diazomethane ring- expands to 1-phenyl-l//-l-benzazepine-2,4,5-trione is incorrect the product is in fact the spirooxirane (276) (76ZN(B)1716). 

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