Buchwald–Hartwig Amination Approach for the Synthesis of Functionalized 1,2,3,4‐Tetrahydroacridine Derivatives

Abstract

Electrophilic 1,2,3,4‐tetrahydroacridin‐9‐yl trifluoromethanesulfonates have been prepared and applied for the first time in the synthesis of functionalized tacrines with high efficacy by using the Buchwald–Hartwig amination reaction. Remarkably, secondary, poor nucleophilic, and functionalized amines also reacted efficiently by using our conditions. The versatility and convenience of these highly reactive derivatives is illustrated through their application in other valuable C–C (Sonogashira, Suzuki, and cyanation cross‐coupling), C–S, and C–O bond‐forming reactions under palladium catalysis.

Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents

“…N-Alkylation of 9-aminotacrine proved not to be a reliable method. , A new strategy was devised that involved the use of a novel electrophilic compound, 7-chloro-1,2,3,4-tetrahydroacridin-9-yl trifluoromethanesulfonate ( 5 ) (Scheme ). Starting from commercially available 5-chloroanthranilic acid, 7,9-dichloro-1,2,3,4-tetrahydroacridine ( 3 ) was obtained by Lewis acid-mediated intermolecular cyclodehydration with cyclohexanone. This intermediate was subsequently hydrolyzed using glacial acetic acid at 200 °C in a sealed tube to obtain intermediate 4 .…”

“…Kinetic measurements, together with structural studies, confirmed the success of our strategy. Introduction of the linker was achieved using our optimized microwave assisted Pd-catalysed Buchwald-Hartwig amination procedure 18 to afford the desired terminal alkynes in excellent yields (Scheme 2). Subsequent Sonogashira coupling with methyl 3-benzyloxy-6bromopicolinate 20 proceeded well to generate the corresponding hybrid precursors.…”

Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease

“…All the chemicals, reagents, and solvents were obtained from commercial vendors [Sigma‐Aldrich (St. Louis, MO, USA), Acros Organics (Waltham, MA, USA), and Alfa Aesar, Ward Hill, MA, USA] with ≥ 95% purity and were used without further purification. The tetrahydroacridin‐9‐amine derivatives 7a – c , 8a , 8d , 9a , and 10a are known compounds which were reported earlier . 1 H NMR spectra were obtained and analyzed using a 300‐MHz spectrometer (Bruker ® Avance; Department of Chemistry, University of Waterloo).…”

Metal-free synthesis of functionalized tacrine derivatives and their evaluation for acetyl/butyrylcholinesterase and α-glucosidase inhibition

“…2). 12,13 The molecules synthesized by these methods show better inhibitory activity (IC 50 : AChE = 1.77 ± 0.22 μm, BChE = 19.0 ± 0.43 μm) than tacrine. 11 However, these methods require more reaction time and use metal-based catalysts.…”