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Structural and Computational Investigation of Intramolecular N···H Interactions in α‐ and β‐Fluorinated 7‐Azaindoline Amides
Author(s) -
Brewitz Lennart,
Noda Hidetoshi,
Kumagai Naoya,
Shibasaki Masakatsu
Publication year - 2018
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201701083
Subject(s) - intramolecular force , substituent , chemistry , amide , hydrogen bond , molecule , stereochemistry , nuclear magnetic resonance spectroscopy , organic chemistry
Novel fluorinated N 1 ‐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 N 1 ‐acylated 7‐azaindolines and similar heterocycles, this study is relevant to medicinal chemistry: The results will facilitate the prediction of the predominant conformations of N 1 ‐acylated‐7‐azaindoline‐containing bioactive molecules and thus potentially contribute to drug discovery programs.