Benzazepinones, formation

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. 

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]. 

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... 

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. 

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]. 

A facile approach to the benzazepinones 284 from the nitrone precursors 283 was reported by Eberbach et al. (Equation 41) <2001EJ03313> (see also Scheme 11). Reaction of 283 with base under mild conditions gave 284 in generally high yields, for example, 284 (R1 = R3 = H, R2 = Ph 84%). A complex series of steps was proposed in the formation of 284 involving allene formation, 1,7-dipolar cyclization, and a series of bond cleavage and formation steps... 

The shortcomings of the Beckmann rearrangement at nitrogen as a method to synthesize the isomeric benzazepinones discussed above apply also to the Schmidt method. In this case, another side reaction, the formation of tetrazoles, may occur. The acidic medium used for the rearrangement plays a decisive role in directing the course of the reaction. The rearrangement may in some cases be nonstereospecific. 

Fused Azepines.—Formation. A convenient route to benzazepinones (25) in which the aryl ring has an electron-donating substituent (R) is provided by the cyclization of y-(aryl)propyl isocyanates, using phosphorus oxychloride and stannic chloride.The benzazepine-l,3-dione (27) was synthesized by ring-closure of (26) and hydrolysis of the chloroimide (28) that was formed irradiation of (27) produced mainly dimers at the alkene bond. ... 

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