3-Benzazepinone, synthesis

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). 

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... 

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... 

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... 

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). 

Benzazepinones can be prepared on cross-linked polystyrene by intramolecular Heck reaction (Entry 6, Table 15.35). In the presence of sodium formate, the intramolecular Heck reaction of iodoarenes with alkynes yields methylene benzazepinones (Entry 7, Table 15.35). Surprisingly, when this reaction was performed in solution, the main product (65% yield) was a dehalogenated, non-cyclized benzamide. In the synthesis on cross-linked polystyrene, however, this product was not observed [419]. 

Phenylacetylenes substituted in the ortho -position with tethered amide functionality undergo an intramolecular endo-dig addition of the amide group to the C=C in the presence of 5% (Ph3P)2Pd(OAc)2 and KOH. This methodology is suitable for the synthesis of 3-benzazepinone.80... 

Irie and co-workers have described an improved synthesis of the alkaloid elwesine (dihydrocrinine) (14).8 Application of Tsuda s two-stage method for the preparation of lactams (POCl3, then SnCl4) to the isocyanate that was derived from the 4-arylbutyric acid derivative (12) gave the benzazepinone (13) in 70% yield this compound has already been converted into elwesine. 

DM Floyd, RY Moquin, KS Atwal, SZ Ahmed, SH Spergel, JZ Gougoutas, MF Malley. Synthesis of benzazepinone and 3-methylbenzothiazepinone analogs of diltiazem. J Org Chem 55 5572-5575, 1990. 

J Das, DM Floyd, SM Kimball, RN Patel, JK Thottathil. Chemoenzymatic synthesis of benzazepinone calcium channel blocking agents. Indian J Chem 31B 817-820, 1992. 

To obtain sufficient quantities of benzazepinone 10 for large-scale synthesis of 1, the Yamanouchi process group subsequently turned to the preparation of 10 in a five-step sequence commencing with anthranilic acid 16.33 Acid-mediated esterification of 16 followed by aniline tosylation provided sulfonamide 17, which was subsequently alkylated with 4-chlorobutyronitrile to furnish the jV-(3-cyanopropyl)anthranilate 18. Dieckmann cyclization of 18 with sodium hydride in DMF then established the... 

Barton-Zard pyrrole synthesis, 70, 75 Benzazepine, 70, 145 Benzazepinone, 70, 144... 

Several approaches to the synthesis of the tetrahydrobenzazepine ring system have been described, and excellent methods exist for the preparation of aryl substituted tetrahydrobenzazepines. However, benzazepines that are either unsubstituted or alkyl-substituted on the azepine ring are much less readily obtainable. For instance, the benzazepinone, synthesized by this procedure, was originally isolated, in tow yield, from the mixture of photoproducts obtained from the irradiation of N-[3-(3,4-dimethoxyphenyl)]propyl chloroacetamide. Preparative approaches to the benzazepinones have required multiple steps starting from an N-phenylethylacetamide and involving chloromethylation, cyanide displacement, nitrile solvolysis, hydrolysis to the amino acid and cyclization.7 The f-alkyl derivatives are... 

A new route for the synthesis of 50 (YM087), an arginine vasopressin antagonist, has been reported by Tsunoda et al. <04H(63)1113>. The imidazolobenzazepine 49 was a key intermediate in this new route which involved benzazepinone formation from the amino ester 48 (obtained in turn in two steps from 47) followed by elaboration of the imidazole ring fusion. 

Photocyclization of iV-chloroacetyl amines has been used previously in the synthesis of nitrogen heterocycles, and the reaction of the substituted amine (166) leads to a benzazepinone that can be elaborated to give pseudoprotopine alkaloids. Y-Chloroacetyl derivatives of the seven isomeric indolylethylamines give azepinoindoles and azocinoindoles by photocyclization. Quantum yields for the reaction are correlated with calculated (CNDO/2 and INDO) electron densities, and on this basis mechanisms are suggested the conclusion is that both indole radical cations and indolyl radicals (for the 1-substituted compounds) are... 

The Schmidt rearrangement of a six-membered benzo-fused ketone with sodium azide yielded benzazepinone derivatives en route to the synthesis ofa library of tubulin-polymerization inhibitors (14JME1390).The reaction of N-nitrosoaniUnes 16 with 2-vinyloxirane 17, catalyzed by rhodium (111), followed by Raney-nickel-catalyzed hydrogenation led to a series of benzazepane derivatives 18 via a reductive amination of a proposed aldehyde intermediate (140L1200). 

Seven-membered ring closures via e do-cyclization are by far more widespread than the analogous gndo-modes for five- or six-membered cycles. There are some examples using substructure G (Figure 6.4) as substrate. Joseph and cowoikers [145] reported the synthesis of fused heterocycles bearing a benzazepinone moiety. Tetracycle 202 was obtained in excellent yield starting from indole derivative 201 in the presence of silver salt (Scheme 6.59). 

Joucla, L., Putey, A. and Joseph, B. (2005) Synthesis of fused heterocycles with a benzazepinone moiety via intramolecular Heck coupling. Tetrahedron Lett., 46, 8177-9. 

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