Structural and Computational Investigation of Intramolecular N−H Interactions in α- and β-Fluorinated 7-Azaindoline Amides
2018
Novel fluorinated N1-acylated 7-azaindolines were 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 correlated 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) was varied at the 4-position of the 7-azaindoline scaffold. As these intramolecular interactions also occur in non-fluorinated N1-acylated 7-azaindolines and similar heterocycles, this study is relevant to medicinal chemistry: It will facilitate the prediction of predominant conformations of N1-acylated 7-azaindoline-containing bioactive molecules and thus potentially contribute to drug discovery programs.
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