Calcium‐Catalyzed Synthesis of 1,2‐Disubstituted 3‐Benzazepines

Abstract

A short and highly stereoselective chiral pool synthesis of tetrahydro‐3‐benzazepines as potential drug molecules is described, using simple enantiopure amino acids as the chiral building blocks. Intramolecular Friedel–Crafts alkylation towards seven‐membered rings was achieved with high diastereoselectivity for the first time and accomplished by a biocompatible calcium catalyst. The simple and cost efficient approach allows for the variation of all substituents in the 3‐benzazepine by a change of the substitution pattern in one or more of the reagents, while leaving the general synthetic route unchanged. Furthermore, assignment of the absolute configuration of the 3‐benzazepine derivative is straightforward, based on the amino acid building block employed.

Carbon–Carbon and Carbon–Heteroatom Bond-Forming Transformations Catalyzed by Calcium(II) Triflimide

“…The Niggemann group also reported a stereocontrolled synthesis of benzazepine scaffolds starting from amino acid derivatives (Scheme 4). 11 Compared to their preceding reports, the reaction was conducted in the presence of 10 mol% Ca(NTf 2 ) 2 under microwave irradiation to shorten the reaction times. The desired products were obtained in high yields (up to 96%) with a preferred trans-configuration.…”

A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings

“…Furthermore, benzazepine derivatives are promising bioactive compounds that are generally synthesized in multiple steps, leading to the generation of stoichiometric amounts of waste [16]. They have relevant biological properties, including anxiolytic, dopaminergic, anthelmintic, antimicrobial, antitumor, anti-HIV, bronchodilator, antiarrhythmic activity, among others, and are used in Parkinson's disease treatment [17][18][19][20][21][22][23][24]. These compounds are also potentially good candidates for new drug therapies to treat skin and wounds [25].…”

Route to Functionalized Tetrahydrobenzo[d]azepines via Re2O7-Mediated Intramolecular Friedel–Crafts Reaction

“…The empirical rule for successful substrates is that the aryl group of the benzyl alcohol moiety should not be too much more electron-rich compared to the tethered aryl group to avoid the competing intermolecular reaction. Finally, 1,2-disubstituted 3-benzazepines ( 2ff and 2gg ) could also be synthesized in excellent yields and good diastereoselectivity, another advantage over the acid-catalyzed protocols. , …”

“…The development of mild and more reliable approaches for the syntheses of benzazepines via intramolecular Friedel–Crafts cyclization is highly desirable, considering the limitations of the current methods. As part of our continuing efforts to use Re 2 O 7 /HReO 4 and HFIP for the generation and stabilization of otherwise destabilized carbocations via activation of hydroxy groups in alcohols, , we speculate that this catalyst system could serve as a promising solution due to the simplicity of operation, convenient recyclability of both Re 2 O 7 /HReO 4 and HFIP, , and a significantly enlarged substrate scope that is crucial for studies of structure–activity relationships (SARs) in biological applications.…”