Development, Scope and Mechanisms of Multicomponent Reactions of Asymmetric Electron‐Deficient Alkynes with Amines and Formaldehyde

Abstract

Based on the reactive behaviour of the substrates, two synthetic routes to polysubstituted pyrimidine derivatives are presented herein: 1) A catalyst-free multicomponent reaction of electron-deficient alkynes, aliphatic amines and formaldehyde and 2) Ag(I)-catalyzed synthesis of pyrimidines from electron-deficient alkynes, anilines and formaldehyde by a domino reaction. Under optimized conditions, the multicomponent reactions were accomplished with high regioselectivity and excellent yields. A computational study was carried out by using the B3LYP density functional theory to elucidate the mechanisms of the catalyst-free hydroamination reaction. Calculations showed the activation free energies of aliphatic amines were lower than those of anilines, which is consistent with the experimental results.

Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes and an Unusual Ligand‐Free Copper(II)‐Mediated Intramolecular Cross‐Coupling

“…Cyclizations based on acetylenic esters (ynoates) : The preparation of indoles that have ester substituents at the 3‐position was similarly attempted from N ‐formylanilines 1 and ynoates 24 . The conjugate additions of ortho ‐haloanilines to various β‐substituted ynoates at elevated temperatures in the presence of copper(I) iodide,29 or at room temperature with silver tetrafluoroborate30 or gold salts,31 have been previously reported. Again, the use of the N ‐formylanilines proved expedient for additions to ynoates and these processes proceeded at room temperature without the need for metal additives.…”

Reversed reactivity of anilines with alkynes in the rhodium-catalysed C–H activation/carbonylation tandem

“…However, a three-component reaction of an aniline, an alkyne and an (aromatic) aldehyde to yield 2-substituted quinoline derivatives is a matured transformation in organic synthesis via typical Micheal-type 1,4-conjugate addition 42 43 . A multicomponent reaction of electron-deficient alkynes with amines and formaldehyde leads to polysubstituted pyrimidine derivatives were reported by Jiang and his co-workers and such type of product was not detected in our system 44 . It is very important to note that, in our reaction, paraformaldehyde and/or formalin solution were used as a carbonyl source (without using poisonous CO gas) and the reaction operates in an auto-tandem manner.…”

New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: an overview and current status

“…In a subsequent study, Jiang and co-workers 122 developed two multi-component methodologies towards polysubstituted pyrimidine derivatives 111, 112. In the metal-free approach, electron-deficient alkynes 107, amines 108, 109 and formal-dehyde 110 were coupled to obtain the heterocyclic product in an efficient yield (Scheme 24).…”