Structural and Computational Investigation of Intramolecular N···H Interactions in α‐ and β‐Fluorinated 7‐Azaindoline Amides

Abstract

Novel fluorinated N1‐acylated 7‐azaindolines have been synthesized and their conformations analyzed by X‐ray diffraction and NMR spectroscopy: Unusual intramolecular interactions between the 7‐nitrogen and amide α‐hydrogen atoms were identified. The strength of these interactions correlate with the electron‐withdrawing character of the amide α substituents. A combination of experimental and computational approaches revealed a significant substituent effect when the substituent (H, OMe, F, CN) at the 4‐position of the 7‐azaindoline scaffold was varied. As these intramolecular interactions also occur in non‐fluorinated N1‐acylated 7‐azaindolines and similar heterocycles, this study is relevant to medicinal chemistry: The results will facilitate the prediction of the predominant conformations of N1‐acylated‐7‐azaindoline‐containing bioactive molecules and thus potentially contribute to drug discovery programs.