Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

Abstract

Publications covering a new easy metal-free functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine) under the action of the system of electron-deficient acetylenes (acetylenecarboxylic acid esters, acylacetylenes)/P-nucleophiles (phosphine chalcogenides, H-phosphonates) are reviewed. Special attention is focused on a SNH reaction of the regioselective cross-coupling of pyridines with secondary phosphine chalcogenides triggered by acylacetylenes to give 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as three-modal adjuvants (i) activating the pyridine ring towards P-nucleophiles, (ii) deprotonating the P-H bond and (iii) facilitating the nucleophilic addition of the P-centered anion to a heterocyclic moiety followed by the release of the selectively reduced acetylenes (E-alkenes).

Catalyst- and solvent-free regiospecific SNHAr phosphinylation of pyridines with H-phosphinates mediated by benzoylphenylacetylene

“…Generally, the substituent effects are consistent with those existing in previously considered cases of S N H Ar phosphorylation of azines by PH-acids triggered and driven by electron-deficient acetylenes. 31,32 This might imply the similarity in the mechanism. Indeed, if the initial and key step of the reaction is the reversible formation of the 1,3(4)-dipole intermediate A that resulted from the nucleophilic attack on the pyridine nitrogen at the triple bond (Scheme 4), 31,32 then the donor substituent in the pyridine ring should facilitate the reaction that is really observed in the experiment.…”

“…31,32 This might imply the similarity in the mechanism. Indeed, if the initial and key step of the reaction is the reversible formation of the 1,3(4)-dipole intermediate A that resulted from the nucleophilic attack on the pyridine nitrogen at the triple bond (Scheme 4), 31,32 then the donor substituent in the pyridine ring should facilitate the reaction that is really observed in the experiment. If the second step of the process is the generation of the ion pair B via the quenching of the carbanionic part of intermediate A by the proton of the PH-acid, 31,32 then the acceptor substituent (Ph) in the latter should favor the process that actually takes place here.…”

“…One of the promising routes to address this challenge is the nucleophilic substitution of hydrogen in a heteroaromatic ring, which is actively developing now. [29][30][31][32][33] An advantageous feature of this reaction is that it does not require preliminary functionalization, including halogenation, of the heterocyclic substrate that leads to environmentally dangerous waste.…”

“…Recently, 31,32 we discovered a new type of S N H Ar reaction of azines with P-nucleophiles, the novelty of which is the employment of electron-deficient acetylenes as adjuvants, simultaneously activating the azine ring, deprotonating the P-nucleophiles and oxidizing (aromatizing) the dihydro intermediates. This reaction was distinguished by a fairly wide substrate scope of azines ( pyridines, quinolines, isoquinolines, acridines, and phenanthridines), phosphine chalcogenides (oxides, sulfides, and selenides), and electron-deficient acetylenes (alkyl propiolates, terminal and internal acylacetylenes, and 3-phenylprop-2-ynenitrile).…”

Catalyst-free nucleophilic substitution of hydrogen in quinoline rings by acylethynylpyrroles: stereoselective synthesis of 2-(E-2-acylethenylpyrrolyl)quinolines

“…The major advances and challenges existing in this area were comprehensibly analyzed in reviews by Makosza 1 and Chupakhin, 2 who pioneered this chemistry. Commonly, S N H Ar reactions require three prerequisites [see the previous review and the references therein 3 ]: (i) the electrophilic activation of the aromatic (heteroaromatic) ring, (ii) generation of the attacking anion with strong bases and (iii) aromatization of anionic σ H -adducts or dihydro intermediates by external oxidants. Recently, 3,4 the nucleophilic substitution of hydrogen in non-activated pyridines and their fused derivatives by secondary phosphine chalcogenides under the promotion of electron-deficient acetylenes was achieved (Scheme 1).…”