Selective Synthesis of N-Acylnortropane Derivatives in Palladium-Catalysed Aminocarbonylation

Abstract

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2 PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.

Gas–liquid tubular continuous-flow Pd-catalysed aminocarbonylation process for scalable synthesis of carboxamides

“…Under the previously optimised conditions (80 °C, 3 bar CO, 10 min residence time), only the C–I moiety was reactive, which resulted in the selective formation of monocarbonylated products 5a and 5b with isolated yields of 61% and 86%, respectively. The aminocarbonylation of 5 , using the sterically hindered secondary amine nortropinone ( e ) as biologically relevant nucleophile 25 required the replacement of toluene by DMF as solvent, a two-fold excess of base ([Et 3 N] = 1.2 M) and a longer residence time (30 min). Under these optimised conditions, the nortropinone-derived benzene carboxamide 5e was obtained with 75% isolated yield.…”

Alkyl Levulinates and 2-Methyltetrahydrofuran: Possible Biomass-Based Solvents in Palladium-Catalyzed Aminocarbonylation

“…Based on our former research [ 69 , 70 ], in which XantPhos was used successfully to convert the substrate selectively to the target product in a short reaction time, we decided to apply this rigid bidentate phosphine ligand with a large bite angle to increase the efficiency (e.g., conversion, selectivity) of the model reaction. After changing the triphenylphosphine to XantPhos and carrying out the reaction under ambient conditions (50 °C and 1 bar of CO pressure), complete conversion was detected in the alkyl levulinate solvents, while the reaction was also almost complete in 2-MeTHF (87%) after 6 h.…”

Highly Selective Synthesis of 6-Glyoxylamidoquinoline Derivatives via Palladium-Catalyzed Aminocarbonylation

“…However, when cyclohexylamine ( c ) is used, the selectivity in favor of amide ( 2c ) decreases to 70% (entry 9). Based on our previous results [ 69 , 70 ], the triphenylphosphine was replaced by the bidentate XantPhos to increase the selectivity toward the carboxamide. When the aminocarbonylation of 6-iodoquinoline ( 1 ) with piperidine ( b ) was conducted at 1 bar of CO pressure and at 50 °C in the presence of Pd(OAc) 2 /XantPhos catalysts, the corresponding carboxamide ( 2b ) was formed almost exclusively (95%) (entry 10).…”