[1,5]-Hydride Shift-Cyclization versus C(sp 2 )-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(sp ² )-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-7b H -quinolino [1,2- d ][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp ³ )-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 S _E Ar reaction [C(sp ² )-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 ₅₀ value.