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-(1-ethoxyvinyl)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 Bench-Stable N-Quaternized Ketene N,O-Acetals and Preliminary Evaluation as Reagents in Organic Synthesis

“…As previously disclosed, 2-chloro-, 2-bromo-, and 2-iodopyridine are among the most efficient substrates in the formation of stable pyridinium ketene N , O -acetals (Tables , 1c–e , 2c–e ). Therefore, we began by surveying a broader range of halopyridines.…”

“…Following our initial report, which primarily focused on extensive characterization of these unusual complexes, we desired to broaden the scope and efficiency of N -(1-alkoxyvinyl)­ammonium salt synthesis while simultaneously examining their innate reactivity in useful synthetic transformations. To begin, we revisited our original protocol for synthesizing N -(1-alkoxyvinyl)­pyridinium salts with the aim of systematically evaluating critical parameters including time, temperature, stoichiometry, acid source, solvent, order of reagent addition, and method of purification.…”

“…A brief study was also conducted on the scope of acids ( C ) capable of producing N -(1-ethoxyvinyl)­pyridinium salts D . As a control, we tested triflic anhydride, which would produce TfOH during the purification step; however, no product was formed (entry 18). The strong mineral acid HCl favored N -protonation, whereas H 2 SO 4 led to a complex mixture (entries 23 and 24).…”

“…Though the direct use of pyridines with an electron-donating group at C2 was unsuccessful, it should be noted here that both alkoxy- and amino-substitutions are possible within N -(1-ethoxyvinyl)­pyridinium triflate systems, but they must be prepared via an S N Ar reaction (vide supra, Table ; vide infra, Scheme ). Finally, the strongly nucleophilic N , N -dimethylaminopyridine (DMAP) did not yield any corresponding adducts with either N -atom, which is interesting because related adducts derived from compounds such as N,N -dimethylaniline (vide infra, Scheme ) or aminopyridines (vide infra, Scheme ) were found to be stable.…”

“…Recently, our laboratory discovered a new class of pyridinium salts that contain unusually stable N -quaternized ketene N , O -acetals and, consequently, have the potential of engaging in a variety of useful synthetic transformations . Such compounds are simple to prepare by direct treatment of a pyridine with ethoxyacetylene and triflic acid (Scheme ).…”