Regioselective Nucleophilic Aromatic Substitution: Theoretical and Experimental Insights into 4-Aminoquinazoline...

The 4-aminoquinazoline scaffold is a privileged structure in medicinal chemistry. Regioselective nucleophilic aromatic substitution (S_NAr) for replacing the chlorine atom at the 4-position of 2,4-dichloroquinazoline precursors is well documented in the scientific literature and has proven useful in synthesizing 2-chloro-4-aminoquinazolines and/or 2,4-diaminoquinazolines for various therapeutic applications. While numerous reports describe reaction conditions involving different nucleophiles, solvents, temperatures, and reaction times, discussions on the regioselectivity of the S_NAr step remain scarce. In this study, we combined DFT calculations with 2D-NMR analysis to characterize the structure and understand the electronic factors underlying the regioselective S_NAr of 2,4-dichloroquinazolines for the synthesis of bioactive 4-aminoquinazolines. DFT calculations revealed that the carbon atom at the 4-position of 2,4-dichloroquinazoline has a higher LUMO coefficient, making it more susceptible to nucleophilic attack. This observation aligns with the calculated lower activation energy for nucleophilic attack at this position, supporting the regioselectivity of the reaction. To provide guidance for the structural confirmation of 4-amino-substituted product formation when multiple regioisomers are possible, we employed 2D-NMR methods to verify the 4-position substitution pattern in synthesized bioactive 2-chloro-4-aminoquinazolines. These findings are valuable for future research, as many synthetic reports assume regioselective outcomes without sufficient experimental verification.