1,5]-Hydride Shift-Cyclization versus C(sp2)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines.

Dóra Szalóki Vargáné,Dehai Li,Attila Kiss-Szikszai,Yinghan Chen,Lingxue Tao,Sándor Antus,Tibor Kurtán,László Tóth,Haiyan Zhang,Attila Mándi,Péter Mátyus,Balázs Buglyó

doi:10.3390/molecules25061265

Abstract

Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 μM IC50 value.

Highlights

C-H activation and functionalization of sp3 - and sp2 -hybridized carbons offer atom-economical and step-efficient ways for the preparation of polyfunctionalized condensed heterocycles, which haveMolecules 2020, 25, 1265; doi:10.3390/molecules25061265 www.mdpi.com/journal/moleculesMolecules 2020, 25, x FOR PEER REVIEW MoleculesC-H activation and functionalization of sp3- and sp2-hybridized carbons offer atom-economical and step-efficient ways for the preparation of polyfunctionalized condensed heterocycles, which have been intensely investigated recently [1,2,3,4]
The synthesis of 4-aryl-1,4-benzoxazepine derivatives rac-1a–c, starting materials of the Knoevenagel-[1,5]-hydride shift-cyclization reaction, was achieved in the a simple three-step sequence domino was achieved in a simple three-step from the readily available chroman-4-one, 2-(1-naphthyl)-chroman-4-one [31] and sequence from the readily available, 2-(1-naphthyl)-chroman-4-one
Affording the corresponding 3,4-dihydro-1,4-benzoxazepine-5(2H)-ones rac-8a–c (Scheme 3), which were affording the corresponding 3,4-dihydro-1,4-benzoxazepine-5(2H)-ones rac-8a–c (Scheme 3), which reduced with LiAlH4 under reflux to provide 2,3,4,5-tetrahidro-1,4-benzoxepines

Summary

Introduction

C-H activation and functionalization of sp3 - and sp2 -hybridized carbons offer atom-economical and step-efficient ways for the preparation of polyfunctionalized condensed heterocycles, which have. C-H activation and functionalization of sp3- and sp2-hybridized carbons offer atom-economical and step-efficient ways for the preparation of polyfunctionalized condensed heterocycles, which have been intensely investigated recently [1,2,3,4]. The metal-free sp C-H functionalization via been intensely investigated recently [1,2,3,4]. The metal-free sp C-H functionalization via internal redox internal redox processes or hydride transfer has attracted much attention due to its unique features. Processes or hydride transfer has attracted much attention due to its unique features. The resultant zwitterionic intermediate B can undergo further cyclization producing zwitterionic intermediate B can undergo further cyclization producing condensed heterocycles C

Methods

Results

Conclusion