Abstract
Pd-catalyzed amination of isomeric 2,6-, 2,8-, 4,8- and 4,7-dichloroquinolines was studied using adamantane-containing amines in which substituents at the nitrogen atom differ in bulkiness. The selectivity of the amination of 2,6-dichloroquinoline was very low, substantially better results were obtained with 2,8-dichloroquinoline, and 4,8- and 4,7-dichloroquinolines provided the best yields of the amination products. Diamination of 4,8- and 4,7-dichloroquinolines was carried out with two amines which differ strongly in the bulkiness of the alkyl group. In the majority of cases BINAP ligand was successfully applied, however, it had to be replaced with DavePhos in certain reactions when using the most sterically hindered amine as well as for the diamination reactions.
Highlights
The pharmacological activity of adamantane derivatives is well documented and arises from various factors, the main being their ability to penetrate the lipid layers of membranes and to interact with hydrophobic sites of proteins due to the presence of a rigid lipophilic backbone
The reactions were conducted in boiling dioxane (c = 0.1 M), equimolar amounts of reagents were employed for the synthesis of monoaminosubstituted quinolines, 3–4 equiv. of amine were used to obtain diamino-substituted products
All four amines were studied in the monoamination reactions with each dichloroquinoline, and two amines, namely 1a and 1d, were employed in the diamination processes
Summary
The pharmacological activity of adamantane derivatives is well documented and arises from various factors, the main being their ability to penetrate the lipid layers of membranes and to interact with hydrophobic sites of proteins due to the presence of a rigid lipophilic backbone. There is scarce information about the quinolinyl derivatives of adamantaneamines, as only two publications [5,6] deal with 4-quinolinyl derivatives which demonstrated anti-malarial activity, and one describes the synthesis of 2-quinolinyl-substituted adamantane-1,3-diamine [7] All these compounds were obtained using non-catalytic methods. 4-aminoquinoline derivatives except for one work [33], 4-amino- and especially 4-amino-7chloroquinolines were shown to be potent anti-malarial agents [34,35,36] Taking all these facts into consideration and in view of our interest in the Buchwald-Hartwig amination of heteroaryl halides [37,38,39,40], we decided to study the Pd-catalyzed amination reactions of isomeric dichloroquinolines with selected adamantane-containing amines, which differ in the steric hindrance at the amino group, and to determine the best conditions for the selective mono- and diamination of these hetaryl dichlorides
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