Lewis acid promoted Friedländer condensation reactions between anthranilonitrile and ketones for the synthesis of tacrine and its analogues

Abstract

Nesse trabalho estudou-se a reação de ciclodesidratação entre antranilonitrila e várias cetonas na presença de diferentes ácidos de Lewis não reportados na literatura, para a obtenção de 9-amino-1,2,3,4-tetrahidroacridinas. As reações de ciclodesidratação foram realizadas em condições térmicas empregando-se diferentes solventes e também na ausência de solvente, seguidas de hidrólise alcalina, levando à obtenção dos produtos em bons a excelentes rendimentos após isolamento.The scope of Lewis acid-promoted cyclodehydratation reactions between anthranilonitrile and several ketones, to afford tacrine and its derivatives, was expanded to include the use of various metal chloride salts not reported in the literature. The ability of the Lewis acids to effectively promote the cyclodehydratation between anthranilonitrile and cyclohexanone as the ketone was found to be the following order: InCl 3 > AlCl 3 ~ BF 3 .Et 2 O > FeCl 3 > BiCl 3 ~ SbCl 3 ~ SnCl 2 .2H 2 O. The reactions were performed under both solvent and solvent-free conditions in good to excellent yields. Other Lewis acids screened, such as RuCl 3 , CeCl 3 , NiCl 2 , CoCl 2 .2H 2 O and CsCl were not effective.

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

“…In continuation with our search for new ChE inhibitors based on tacrine units [24,25] as well as the development of new synthetic methods using Lewis acids as catalysts [25e27], we describe in the present study, the synthesis of a novel class of hybrids tacrine-2,4,5-triphenyl-1H-imidazole (or tacrine-lophine hybrids) as inhibitors of AChE and BuChE (Scheme 1). Compounds containing imidazole moiety have many pharmacological properties and play important roles in biochemical processes [28,29].…”

11-[Bis(trimethylsilyl)amino]-2,4-bis(trimethylsilyl)-7,8,9,10-tetrahydro-6H-cyclohepta[1,2-b]quinoline

“…Tacrine (9-amino-1,2,3,4-tetrahydroacridine) inhibits acetylcholinesterase, and has been used as a drug for treating Alzheimer's disease (Recanatini et al, 2000;Peçanha et al, 2001;Katzman, 1986;Shutske et al, 1988) since 1993. However, serious side-effects have restricted its use against this disease (McKenna et al, 1997;da Costa et al, 2009). In recent years, several groups have focused upon synthesizing new tacrine derivatives and exploring their inhibitory effects on cancer cell lines and acetylcholinesterase in the desire to minimize side effects.…”

2,2′-(2,6-Pyridinediyl)diquinoline

“…Interestingly, both the binding affinity and the platination activity seem to be determined by the extension of the aromatic surface of the terpyridine derivative. One of the ligands used in that work was 2,2′-(2,6pyridinediyl)bis-quinoline, synthesized through the Friedländer condensation (Da Costa et al, 2009;Sridharan et al, 2009) between 2,6-diacetylpyridine and 2-nitrobenzaldehyde. We now report the crystal structure of this aromatic ligand.…”