H-bond network-facilitated, diversity-oriented, green synthesis of valuable organic compounds via atom-economic, regio- and stereo-selective reactions involving ynamides and anilines

Abstract

Diversity-oriented synthesis (DOS) enables synthetic organic chemists to fabricate structurally diverse classes of molecules, which is highly desirable in the context of medicinal chemistry, thus leading to drug discovery. Herein, we report the H-bonding network-mediated DOS of five structurally diverse classes of molecules, such as acetimidamides, ketene N,N-acetals, α-arylenamides, some heterocycles, such as quinolines, and 3,4-dihydroquinolin-4-ols, starting from readily available ynamides and anilines in the presence of HFIP as the only reagent/solvent. 2-Amidoindoles were also synthesized via a one-pot, two-step process starting from ynamides and primary anilines using CuCl₂. The significant benefits of this protocol compared with the previously established synthetic methods are the following: (a) a cost-effective, straightforward, and unified approach for diversity-oriented, green synthesis of various classes of valuable molecules from ynamides and all types of aromatic amines (1°, 2°, and 3°); (b) a metal-free, environmentally friendly, and scalable protocol; (c) mild reaction conditions; (d) 100% atom-economic transformations; (e) HFIP being the sole reagent necessary for the transformations; (f) the dual functionality of HFIP as both a Brønsted acid and a solvent; (g) the regeneration of HFIP post-reaction and its straightforward and effective recovery from the reaction mixture through distillation; (h) the reusability and efficient recyclability of HFIP without compromising the subsequent reaction's results; and (i) the ability to obtain pure products under various conditions without the need for column chromatography (green synthesis).