Dual Reactivity of the Alkaloid Thebaine and Its Derivatives Towards Acetylenes and the Synthetic Potential Thereof

A unique diene moiety of the alkaloid thebaine enables its successful application in the Diels–Alder reaction with ethylene derivatives for producing the adducts that can serve as precursors for a whole class of opioids used in medicine. The interaction of thebaine with acetylenes as an alternative approach to analogous adducts that offers an additional opportunity for their functionalization has received undeservedly little attention. The current review is devoted to these reactions and their synthetic potential.

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the SNAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O2, the expected dihydroquinolines were formed, while in the presence of O2, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed.

A Mechanistic Analysis of Trimethylanilinium Salt Degradation: Implications for Methylation and Cross-coupling Applications

<i>N,N,N</i>-trimethylanilinium salts are known to display dual reactivity through both the aryl group and the <i>N</i>-methyl groups. These salts have thus been widely applied in cross-coupling, aryl etherification, fluorine radiolabelling, phase-transfer catalysis, supramolecular recognition, polymer design, and (more recently) methylation. However, their application as electrophilic methylating reagents remains somewhat underexplored, and an understanding of their arylation versus methylation reactivities is lacking. This study presents a mechanistic degradation analysis of <i>N,N,N</i>-trimethylanilinium salts and highlights the implications for synthetic applications of this important class of salts. Kinetic degradation studies, in both solid state and solution phases, have delivered insights into the physical and chemical parameters affecting anilinium salt stability. ¹H NMR kinetic analysis of salt degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with a closed-shell S_N2-centred degradative pathway, and methyl iodide being the key reactive species in applied methylation procedures. Furthermore, the effect of halide and non-nucleophilic counterions on salt degradation has been investigated, along with deuterium isotope and solvent effects. Finally, new mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-methylation and in improved cross-coupling strategies.

A Mechanistic Analysis of Trimethylanilinium Salt Degradation: Implications for Methylation and Cross-coupling Applications

<i>N,N,N</i>-trimethylanilinium salts are known to display dual reactivity through both the aryl group and the <i>N</i>-methyl groups. These salts have thus been widely applied in cross-coupling, aryl etherification, fluorine radiolabelling, phase-transfer catalysis, supramolecular recognition, polymer design, and (more recently) methylation. However, their application as electrophilic methylating reagents remains somewhat underexplored, and an understanding of their arylation versus methylation reactivities is lacking. This study presents a mechanistic degradation analysis of <i>N,N,N</i>-trimethylanilinium salts and highlights the implications for synthetic applications of this important class of salts. Kinetic degradation studies, in both solid state and solution phases, have delivered insights into the physical and chemical parameters affecting anilinium salt stability. ¹H NMR kinetic analysis of salt degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with a closed-shell S_N2-centred degradative pathway, and methyl iodide being the key reactive species in applied methylation procedures. Furthermore, the effect of halide and non-nucleophilic counterions on salt degradation has been investigated, along with deuterium isotope and solvent effects. Finally, new mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-methylation and in improved cross-coupling strategies.

Direct oxidative carboxylation of terminal olefins to cyclic carbonates by tungstate assisted-tandem catalysis

Tungstate catalysts are well established for olefin epoxidation reactions, while their catalytic activity for CO2 insertion in epoxides is a more recent discovery. This dual reactivity of tungstate prompted the...

Trialkylammonium Salt Degradation: Implications for Methylation and Cross-coupling

Trialkylammonium (most notably N,N,N-trimethylanilinium) salts are known to display dual reactivity through both the aryl group and the N-methyl groups. These salts have thus been widely applied in cross-coupling, aryl...