Dynamic and Static Conformational Analysis of Acylated Tetrahydrobenzazepines

Abstract

A detailed high-field NMR analysis of several acylated tetrahydrobenzazepines, supported by molecular mechanics calculations, indicates that the heterocyclic ring in these compounds exists in a chair conformation, with the carbonyl oriented anti to the aryl moiety in the dominant rotamer. Surprisingly, ring methylenes are typically diastereotopic at room temperature, as the barriers for the process of enantiomerization of the seven-membered ring are much higher than expected. It is shown that ring inversion is correlated (but not concerted) with rotation of the amide moiety, as the carbonyl is forced out of conjugation with the nitrogen in the transition state.

On the Conformation of 8‐Membered Ring Heterocycles – Dynamic and Static Conformational Analysis of Acylated Hexahydrobenzazocines

“…This suggested a rather high energy barrier between two enantiomeric species resulting from a ring flip of the seven-membered ring. Subsequently [2] we reported a detailed NMR study of several such tetrahydrobenzazepines, in which we established the ground state conformation of this class of heterocycles and explained the reason for the very large barrier for their ring epimerization. Specifically, the latter process is blocked by the interaction of the aromatic ring and the acyl substituent; in order to enable this process, the acyl group has to partially rotate out of coplanarity with the nitrogen, thus incurring a high energetic cost.…”

Application of Ring-Closing Metathesis for the Synthesis of Benzo[3,4]azepino[1,2-b]isoquinolin-9-ones

“…1,2) Conformation studies and synthesis of medium-sized heterocyclic compounds, which have been investigated as the scaffolds of many biologically interesting structures, have received more attention. [3][4][5] Recently, we studied the synthesis of 3-arylisoquinoline derivatives such as indeno [1,2-c]isoquinolines, 6,7) isoindolo [2,1-b]isoquinolines, 8) benz[b]oxepines 9) and benzo-[c]phenanthridinones 10) as constrained structures through molecular modeling to find plausible antitumor agents. The diversely rigidified 3-arylisoquinoline analogs exhibited promising cytotoxicities and topoisomerase I inhibitory activities.…”

“…12) Seven-membered heterocyclic rings are considered attractive molecules due to the points of structural determination of natural products as well as their interesting pharmacological actions. [3][4][5] In this paper we applied RCM [13][14][15][16][17][18][19][20][21][22][23][24][25][26] for the formation of seven-membered benzo [3,4]azepino [1,2-b]isoquinolinone 5, and the retrosynthetic pathway of benzo [3,4]azepino [1,2-b]isoquinolinone 5 is depicted in Chart 1. The coupling reaction of toluamide 7 with benzonitrile 8 afforded the 3-arylisoquinolinone 6, which could be modified to diene 4 as a key intermediate for the RCM reaction.…”

“…In conclusion, cycloaddition reaction between toluamides 7a, b and benzonitriles 8a, b was utilized to prepare the 3-arylisoquinolines 6a, b, which retain the main template for the RCM reaction, to construct the seven-membered heterocyclic compounds, benzo [3,4]azepino [1,2-b]isoquinolinones 5a, b. The conventional transformation of 3-arylisoquinolines 6a, b to dienes 4a, b was carried out and the subsequent RCM reaction furnished the desired benzo [3,4]azepino [1,2-b]isoquinolinones 5a, b in 66% and 85% yield, respectively.…”

“…The conventional transformation of 3-arylisoquinolines 6a, b to dienes 4a, b was carried out and the subsequent RCM reaction furnished the desired benzo [3,4]azepino [1,2-b]isoquinolinones 5a, b in 66% and 85% yield, respectively. We believe that the RCM reaction could be an efficient method for the preparation of heterocyclic medium-sized rings.…”