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.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

“…However, there are circumstances where this inherent preference can be overridden in favor of the gauche conformation, which for a simple α-fluoromethyl amide has been calculated to be ∼6 kcal/mol higher in energy than the trans conformer, while for the α,α-difluoromethyl homologue the energy of the conformation that places the C–H and N–H in a syn relationship is ∼4.5 kcal/mol higher (Figure ). Under these circumstances, α-fluoromethylamides and, particularly, α,α-difluoromethylamides, offer an opportunity to function as urea mimetics, as illustrated by the solid state structure of 416 which crystallizes in the conformation shown, stabilized by close contacts between both the N–H and C–H hydrogen atoms and the pendent carbamate oxygen atom. The bistrifluoromethylamide 417 and monotrifluoromethylamide 418 behave in a similar fashion, with the C–H to oxygen H-bond in 418 shorter than that in 417 , reflecting the poorer H-bond donor effects of this motif, anticipated based on the differences in electron withdrawing effects and polarizability .…”

“…The bistrifluoromethylamide 417 and monotrifluoromethylamide 418 behave in a similar fashion, with the C–H to oxygen H-bond in 418 shorter than that in 417 , reflecting the poorer H-bond donor effects of this motif, anticipated based on the differences in electron withdrawing effects and polarizability . These molecules adopt conformations comparable to that observed with the thiourea 419 , and fluorinated acetanilides have been exploited with some success as organocatalysts based on the anticipation that they would recapitulate the effects of ureas and urea mimics. , However, the α-fluoro derivatives are more active catalysts than the α,α-difluoro analogues, perhaps surprising based on the calculated H-bond strengths which have been estimated to be ∼3.0 kcal/mol for the α-fluoro derivatives and ∼4.0 kcal/mol for the bis-CF 3 amides, with the latter more capable of overcoming the natural bias toward a conformation in which the F and amide and CO are in a trans -periplanar arrangement …”

Japan Prize: A. Yoshino / Merck–Banyu Lectureship: N. Kumagai / DECHEMA Prize: T. Noël

“…Kumagai's research interests include the development of new methodologies in catalysis, and the design and synthesis of novel molecular architectures. His report on the conformations of fluorinated 7‐azaindolines was featured on the cover of the European Journal of Organic Chemistry , and he has reported in Chemistry—A European Journal on the direct catalytic asymmetric aldol reaction of functionalized thioamides …”

Development of Catalytic Enantioselective Mannich Reactions Using Esters

“…The asymmetric Mannich reaction of simple esters with imines is one of the most important methods to synthesize optically active β-amino esters directly without any redox process; such compounds are found in many natural products and drug structures. Although catalytic enantioselective Mannich reactions of functionalized amides have been developed recently, − catalytic enantioselective Mannich reactions of simple esters such as alkyl acetates are still difficult and have not yet been achieved, and stoichiometric amounts of strong bases and chiral auxiliaries have always been employed for asymmetric Mannich reactions of the esters. − However, the simple esters are stable, readily available, and often employed as solvents in organic synthesis; therefore, they are promising pronucleophiles for the reactions. Our group has been focusing on developing strong Brønsted base-catalyzed reactions and has realized catalytic enantioselective 1,4-addition reactions of weakly acidic carbon pronucleophiles including simple amides and esters. − The key to the success was designing strongly basic reaction intermediatestermed the “product base.” − Recently, we reported catalytic enantioselective Mannich reactions of simple amides by using a potassium salt of chiral bisoxazoline (Box) as a chiral ligand .…”