Synthesis of Methyl 7,9-Dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate and Its Analogues

Abstract

A high-yielding five-step synthesis of the title compound, methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate, starting from 2,4-dimethylaniline was developed. This synthesis involved N-alkylation of 2,4-dimethylaniline with ethyl 4-bromobutyrate to obtain ethyl 4-[(2,4-dimethylphenyl)amino]butanoate. Carbamoylation of the latter followed by hydrolysis of the resulting ester provided 4-[(2,4-dimethylphenyl)(methoxycarbonyl)amino]butanoic acid. Activation of the carboxylic acid using thionyl chloride followed by intramolecular cyclization via a Friedel-Crafts reaction using aluminum trichloride provided the title compound in good yield. Analogues of the title compound were also prepared similarly.

Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene

“…Crystals suitable for X-ray analysis were obtained from dissolving 11 in CH 2 Cl 2 followed by the addition of MeOH.The X-ray structure of complex 11 clearly shows that the aryl ring and the palladium still remain positioned cis and exo to the norbornyl group (Figure 3, left). Interestingly, the d 8 Pd center possesses a square-planar geometry with PPh 3 , iodide, norbornyl group, and the bromo substituent. This is in contrast with the literature reported analogue (complex 12) 28 with simple NBE, where the η 2 coordination with the C(5)− C(6) π bond occupies one of the four coordination sites (Figure 3 a weakly coordinating bromo substituent can be considered as a "built-in" L-type ligand into NBE, which may have some implications in catalysis (vide infra).…”

“…In addition, vicinal difunctionalized arenes are needed with these methods. For comparison, the use of intramolecular C–H functionalization to construct the C–C bond in THBAs, via either Friedel–Crafts or transition-metal catalysis, , avoids complex arene precursors and simplifies the synthesis (Scheme , middle). Although they clearly represent more attractive strategies to access THBAs, the availability of the corresponding elaborated aniline substrates cannot be ignored.…”