Synthesis, chemistry and photochemical substitutions of 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ones

Abstract

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

Preparation of α,β-Unsaturated Ketones Bearing a Trifluoromethyl Group and Their Application in Organic Synthesis

“…There are two general approaches: 1) fluorination of an existing heterocyclic ring including functional group transformations [4], for example transformation of a carboxy moiety to a trifluoromethyl group [5] or the trifluoromethylation of heterocycles using CF 3 Cu [6,7] or CF 3 radicals [8,9]. 2) construction of heterocyclic rings using fluorinated synthons.…”

Synthesis of Trifluoromethyl Pyrroles and Their Benzo Analogues

“…Several other photochemical trifluoromethylations by trifluoroiodomethane were reported. From the tricyclic pyr-role 8, the regioisomeric substitution products 9 and 10 were formed, 10 and from the substituted pyrroles 11 and 13 the 2-trifluoromethylpyrroles 12 11 and 14 12 were prepared in moderate and good yields, respectively (Scheme 3).…”

“…In contrast, Nbenzyl-and N-(4-tolyl)-substituted pyrroles 1c and 1d afforded the corresponding derivatives 2c and 2d in 71% and 91% yields, respectively (Table 1, entries 3 and 4). 10…”

Synthesis of fluorofurans and perfluoroalkylfurans

“…and 19% at 160 8C (Table 2) [43][44][45][46][47][48][49][50][51][52][53][54]. Upon using Te(CF 3 ) 2 as a trifluoromethylation agent the yield of a-trifluoromethylfuran increases.…”