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

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.