Synthesis of Bench-Stable N-Quaternized Ketene N,O-Acetals and Preliminary Evaluation as Reagents in Organic Synthesis

Abstract

N-Quaternized ketene N,O-acetals are typically an unstable, transient class of compounds most commonly observed as reactive intermediates. In this report, we describe a general synthetic approach to a variety of bench-stable N-quaternized ketene N,O-acetals via treatment of pyridine or aniline bases with acetylenic ethers and an appropriate Brønsted or Lewis acid (triflic acid, triflimide, or scandium(III) triflate). The resulting pyridinium and anilinium salts can be used as reagents or synthetic intermediates in multiple reaction types. For example, N-(1ethoxyvinyl)pyridinium or anilinium salts can thermally release highly reactive O-ethyl ketenium ions for use in acid catalyst-free electrophilic aromatic substitutions. N-(1-Ethoxyvinyl)-2-halopyridinium salts can be employed in peptide couplings as a derivative of Mukaiyama reagents or react with amines in nucleophilic aromatic substitutions under mild conditions. These preliminary reactions illustrate the broad potential of these currently understudied compounds in organic synthesis.

Synthesis of 1-(1-Arylvinyl)pyridin-2(1H)-ones from Ketones and 2-Fluoropyridine

“… Very recently, Majireck reported the pyridination of alkynes in the presence of TfOH (eq ). However, this system is limited to alkynes that contain electron-donating groups such as OMe, , and pyridinium salts are notwhen observed using phenylacetylene (eq ). Herein, we describe the synthesis of 1-(1-arylvinyl)­pyridin-2­( 1H )-ones from acetophenones that contain electron-donating or electron-withdrawing groups at the benzene ring.…”

“…Conducting the reaction with TfOH as an additive, which is generated 2-F-Py·HOTf in situ, did not improve the yield of 4 dramatically. Similar to the result of Majireck et al, the reactions of aryl alkynes 1g′ and 1k′ with TfOH and 2-fluoropyridine did not effectively afford vinyl pyridones. These results suggest that it is not very likely that both vinyl triflates ( 3 ) and vinyl cations play major roles as intermediates in this transformation (Scheme ).…”

Synthesis and crystal structure of a bench-stable pyridinium ketene hemiaminal: 1-(1-ethoxyethenyl)-2-[methyl(phenyl)amino]pyridin-1-ium trifluoromethanesulfonate

“…access to over forty bench-stable examples of this rare class of compounds (McConnell et al, 2021). However, to date there has been only one published X-ray crystal structure (Fig.…”

“…Pyridinium ketene hemiaminals are an emerging class of reagents in organic synthesis that are able to engage in a variety of reaction modes such as electrophilic aromatic substitutions, nucleophilic aromatic substitutions (S N Ar), and amidations (Shapiro et al, 2018;McConnell et al, 2021). As part of our ongoing efforts to explore the use of these compounds in valuable synthetic applications, we have sought to employ 2-halopyridinium ketene hemiaminals as facile electrophiles in mild S N Ar reactions with amine nucleophiles, en route to the bioactive 2-aminopyridine products such as IV (Fig.…”

“…A sealed 0.5-2.0 mL Biotage microwave vial was charged with potassium carbonate (69 mg, 0.5 mmol), freshly prepared 2-chloropyridinium ketene hemiaminal I (167 mg, 0.5 mmol) (McConnell et al, 2021) and dichloromethane (1 mL). While stirring the resulting suspension at room temperature, N-methylaniline (0.054 mL, 0.5 mmol) was slowly added.…”