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

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-...

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Main Authors:	Dóra Szalóki Vargáné, László Tóth, Balázs Buglyó, Attila Kiss-Szikszai, Attila Mándi, Péter Mátyus, Sándor Antus, Yinghan Chen, Dehai Li, Lingxue Tao, Haiyan Zhang, Tibor Kurtán
Format:	Article
Language:	English
Published:	MDPI AG 2020-03-01
Series:	Molecules
Subjects:	domino knoevenagel-[1,5]-hydride shift-cyclization 1,4-benzoxazepine 1,5-benzoxazepine tddft-ecd calculation acetylcholinesterase inhibitory activity
Online Access:	https://www.mdpi.com/1420-3049/25/6/1265

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record_format	Article
spelling	doaj-7ec6617f417c48579689a8d1644384a82020-11-25T02:01:59ZengMDPI AGMolecules1420-30492020-03-01256126510.3390/molecules25061265molecules25061265[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-BenzoxazepinesDóra Szalóki Vargáné0László Tóth1Balázs Buglyó2Attila Kiss-Szikszai3Attila Mándi4Péter Mátyus5Sándor Antus6Yinghan Chen7Dehai Li8Lingxue Tao9Haiyan Zhang10Tibor Kurtán11Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryInstitute of Digital Health Sciences, Faculty of Health and Public Services, Semmelweis University, Ferenc tér 15, Budapest 1094, HungaryDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, ChinaCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, ChinaDepartment of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, HungaryDomino cyclization reactions of <i>N</i>-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp<sup>2</sup>)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of <i>N</i>-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7b<i>H</i>-quinolino [1,2-<i>d</i>][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp<sup>3</sup>)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-<i>endo</i> 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 <i>N</i>-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an S<sub>E</sub>Ar reaction [C(sp<sup>2</sup>)-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 IC<sub>50</sub> value.https://www.mdpi.com/1420-3049/25/6/1265domino knoevenagel-[1,5]-hydride shift-cyclization1,4-benzoxazepine1,5-benzoxazepinetddft-ecd calculationacetylcholinesterase inhibitory activity
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Dóra Szalóki Vargáné László Tóth Balázs Buglyó Attila Kiss-Szikszai Attila Mándi Péter Mátyus Sándor Antus Yinghan Chen Dehai Li Lingxue Tao Haiyan Zhang Tibor Kurtán
spellingShingle	Dóra Szalóki Vargáné László Tóth Balázs Buglyó Attila Kiss-Szikszai Attila Mándi Péter Mátyus Sándor Antus Yinghan Chen Dehai Li Lingxue Tao Haiyan Zhang Tibor Kurtán [1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines Molecules domino knoevenagel-[1,5]-hydride shift-cyclization 1,4-benzoxazepine 1,5-benzoxazepine tddft-ecd calculation acetylcholinesterase inhibitory activity
author_facet	Dóra Szalóki Vargáné László Tóth Balázs Buglyó Attila Kiss-Szikszai Attila Mándi Péter Mátyus Sándor Antus Yinghan Chen Dehai Li Lingxue Tao Haiyan Zhang Tibor Kurtán
author_sort	Dóra Szalóki Vargáné
title	[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
title_short	[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
title_full	[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
title_fullStr	[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
title_full_unstemmed	[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
title_sort	[1,5]-hydride shift-cyclization <i>versus</i> c(sp<sup>2</sup>)-h functionalization in the knoevenagel-cyclization domino reactions of 1,4- and 1,5-benzoxazepines
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2020-03-01
description	Domino cyclization reactions of <i>N</i>-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp<sup>2</sup>)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of <i>N</i>-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7b<i>H</i>-quinolino [1,2-<i>d</i>][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp<sup>3</sup>)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-<i>endo</i> 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 <i>N</i>-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an S<sub>E</sub>Ar reaction [C(sp<sup>2</sup>)-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 IC<sub>50</sub> value.
topic	domino knoevenagel-[1,5]-hydride shift-cyclization 1,4-benzoxazepine 1,5-benzoxazepine tddft-ecd calculation acetylcholinesterase inhibitory activity
url	https://www.mdpi.com/1420-3049/25/6/1265
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[1,5]-Hydride Shift-Cyclization <i>versus</i> C(sp<sup>2</sup>)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines

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