Assembly of 4-Aminoquinolines via Palladium Catalysis:  A Mild and Convenient Alternative to S_NAr Methodology

Abstract

4-aminoquinolines, classically prepared via SNAr chemistry from an amine and 4-haloquinoline, are important scaffolds in medicinal chemistry. Interest in these compounds prompted us to explore palladium catalysis as an alternative to the existing methods for their preparation. Initial results followed by an iterative screening paradigm confirmed Pd(OAc)2/DPEphos/K3PO4 as a mild and convenient alternative for the formation of the C-N bond in 4-aminoquinolines. A description of the screen and the scope of this methodology are discussed herein.

Development ofN-Methyl-(2-arylquinolin-4-yl)oxypropanamides as Leads to PET Radioligands for Translocator Protein (18 kDa)

“…A similar reaction with palladium catalysis 50 was used to prepare the analogous ligand with X = NH ( 14 ) (Scheme 3). The required amide 13 was readily prepared from 2-bromo- N -methyl- N -phenylpropanamide by conversion into the azide followed by reduction.…”

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle

“…The replacement of chloride by various amino groups was achieved by 2 different means. When an amino group is attached to the flanking end of the alkyl chain, a direct nucleophilic aromatic addition-elimination reaction (S N Ar) is able to convert 3 to the corresponding aminoquinoline ( 5 or 6 ) at elevated temperature (Gong et al., 2013); in contrast, when an amino group is attached to a secondary position such as 19 , a palladium catalyzed amination reaction proved to be more effective (Margolis et al., 2007). The addition of the styryl group, the trans -selective olefination reaction of 2-methylquinoline was accomplished by mixing desired aldehyde with quinoline in the presence of p -toluenesulfonamide and the reaction proceeded through an enamine intermediate (Yan et al., 2011).…”

DMAP‐[2.2]paracyclophane: Observation of an Unusual C–C Insertion

“…Due to the inertness of the substrate, this reaction proved to be very difficult to perform both under thermal activation and metal-catalysis conditions. [17] Optimal results were obtained by heating triflate 13 to reflux in pure pyrrolidine; these conditions enabled full conversion of 13 into 14, but only after an extended period of time (ca. 10 d).…”