A series of 6,ll-dihydro-5R-pyrrolo [2,l-b][3]benzazepin-ll-ones, 4, has been prepared as intermediates for potential CNS drugs. Substituents in the pyrrole ring of 4 were introduced by Friedel-Crafts cyclization of pyrrole-substituted l-(2-phenethyl)pyrrole-2-carboxylic acid derivatives (6) and by electrophilic substitution on the parent ketone 4a. Substituents in the benzene ring of 4 were introduced by Friedel-Crafts cyclization of substituted 2-(2-pyrrol-l-ylethyl)benzoic acids (12). Novel and efficient photochemical reactions were discovered for the direct introduction of the cyano and trifluoromethyl groups into the pyrrole ring of 4a. The latter reaction was extended to yield a series of trifluoromethylated heterocycles. Pyrrolo[2,l-6][3]benzazepin-ll-ones Scheme I r4 *-fFX jsr' SOCl2 or CI2CHOMeI, total synthesis of the ring system; II, introduction of substituents into the parent ketone 4; and III, modification of substituents introduced in I or II. The major successes and difficulties encountered in these approaches are detailed below.1.1 Total Synthesis of Pyrrole-Substituted Ketones (4, X , Y = H). The synthesis of the requisite acid derivatives 6 was carried out by three methods as summarized in Scheme I. Method A has already been de-scribed7 and is quite satisfactory as long as the group X is resistant to catalytic hydrogenation. Method B, the alkylation of a substituted pyrrole-2-carboxylic ester with 2-phenethyl bromide, was also found to be a very satisfactory route to the esters 6.1, particularly when X was a strong electron-withdrawing group. When X was less electron withdrawing, it was advantageous to use phenethyl tosylate to minimize competitive elimination to form styrene.Method C was used to prepare ester 6.1h and, although quite satisfactory, was not used extensively. The preparation of the 4-substituted pyrrole-2-carboxylates was generally carried out by the recent method of Belanger8

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The synthesis and resolution of (+/-)-3-methoxycyproheptadine [(+/-)-4] are described. As a peripheral serotonin antagonist, (+/-)-4 was found to be one-half as potent as cyproheptadine (1b). The peripheral anticholinergic and antihistaminic activities as well as the orexigenic property of (+/-)-4 are less than those of 1b. A further comparison of the enantiomers (+)-4 and (-)-4 shows that all of the anticholinergic activity of (+/-)-4 resides solely in the dextrorotatory enantiomer, (+)-4, while the antiserotonin activity, which is similar to that of 1b, resides in the levorotatory enantiomer, (-)-4. Antihistaminic and orexigenic activity also resides in (-)-4 but these properties are reduced compared to those of 1b.

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