Metal- and Solvent-Free Multicomponent Decarboxylative A³-Coupling for the Synthesis of Propargylamines: Experimental, Computational, and Biological Investigations

Abstract

Decarboxylative A 3 -coupling of ortho-hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed methodology provided a waste-free method for the synthesis of hydroxylated propargylamines which are versatile precursors for various bioactive heterocyclic scaffolds. The experimental and density functional theory studies revealed that the in situ-formed ortho-quinonoid intermediate (formed from ortho-hydroxybenzaldehyde and amine) undergoes a concerted Eschweiler−Clarke type decarboxylation with alkynoic acids. The synthesized compounds were evaluated for MAO-A, MAO-B, and AChE inhibitory activities as potential drug candidates for the treatment of various neurological disorders. Compound 4f was found to be the most potent and selective MAO-B (high selectivity over MAO-A) and AChE inhibitor in the series with IC 50 values of 4.27 ± 0.07 and 0.79 ± 0.03 μM, respectively.

Glyoxylic Acid: A Carboxyl Group‐Assisted Metal‐Free Decarboxylative Reaction Toward Propargylamines

“…Concerning the decarboxylative process, heating to 95 °C resulted in an increase of the yield from 78 % to 86 % (entry 10). A lower temperature (60 °C) did not facilitate this transformation (entry 11), which is similar to the metal‐free A 3 ‐coupling [7,8c] . These results indicated that higher temperature was essential for the reaction.…”

Metal‐Free Decarboxylation of α,β‐Unsaturated Carboxylic Acids for Carbon–Carbon and Carbon–Heteroatom Coupling Reactions

“…In 2020, Kumar and co‐workers reported a metal‐ and solvent‐ free multicomponent decarboxylative A 3 ‐coupling for the synthesis of propargylamines using ortho ‐hydroxybenzaldehydes, secondary amines and propiolic acids as the starting materials [22] . The experimental and DFT studies revealed that an in situ formed ortho ‐quinonoid intermediate 13 from an ortho hydroxy‐benzaldehyde and an amine undergoes a concerted Eschweiler‐Clarke type decarboxylation with propiolic acids (Scheme 10).…”

Metal‐Free Multicomponent Construction of Tetrahydroisoquinoline‐Indole Derivatives via In Situ Generated ortho‐Quinonoid Intermediate

“…This reaction proceeds efficiently in the presence of PPh 3 as ligand and acetic acid as additive (Scheme 1b). During our study on multicomponent A 3 ‐type coupling [15] between ortho ‐hydroxybenzaldehydes, amines and alkynoic acids, we observed that the presence of ortho ‐OH substituent on benzaldehyde ring is crucial for the formation of product and reaction could proceed even under metal‐free conditions. In the present research work, we envisaged that MCR between ortho ‐hydroxybenzaldehydes, THIQs and indoles can lead to a metal‐free entry for the construction of THIQ‐indole derivatives via simultaneous N ‐benzylation and C(1)‐substitution.…”

“…In continuation of our research work towards developing ecofriendly approaches for the synthesis of diverse biologically active molecules, [15,17] we herein describe metal‐ and ligand‐free multicomponent coupling for the synthesis of THIQ‐indole derivatives (Scheme 1c) under solvent‐free conditions. We carried out experimental and DFT calculations wherein it was observed that initially THIQ and ortho ‐hydroxybenzaldehyde forms an ortho ‐quinonoid species which in situ reacts with indole to form THIQ‐indole derivatives.…”