[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
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
Affiliations
Dóra Szalóki Vargáné
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
László Tóth
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
Balázs Buglyó
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
Attila Kiss-Szikszai
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
Attila Mándi
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
Péter Mátyus
Institute of Digital Health Sciences, Faculty of Health and Public Services, Semmelweis University, Ferenc tér 15, Budapest 1094, Hungary
Sándor Antus
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
Yinghan Chen
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
Dehai Li
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
Lingxue Tao
CAS 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, China
Haiyan Zhang
CAS 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, China
Tibor Kurtán
Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, Debrecen 4002, Hungary
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.
