N-Substituted pyridinium salts constitute one of the most valuable reagent classes in organic synthesis, due to their versatility and ease of use. Herein we report a preliminary synthesis and detailed structural analysis of several N-(1-ethoxyvinyl)pyridinium triflates, an unusual class of pyridinium salts with potentially broad use as a reagent in organic synthesis. Treatment of pyridines with trifluoromethane sulfonic acid and ethoxyacetylene generates stable, isolable adducts which have been

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... extensively characterized, due to their novelty. Three-dimensional structural stability is perpetuated by an array of C-H•••O hydrogen bonds involving oxygen atoms from the -SO 3 groups of the triflate anion, and hydrogen atoms from the aromatic ring and vinyl group of the pyridinium cation. Predictions from density functional theory calculations of the energy landscape for rotation about the exocyclic C-N bond of 2-chloro-1-(1-ethoxyvinyl)pyridine-1-ium trifluoromethanesulfonate (7) and 1-(1-ethoxyvinyl)pyridine-1-ium trifluoromethanesulfonate (16) are also reported. Notably, the predicted global energy minimum of 7 was nearly identical to that found within the crystal structure. Molecules 2018, 23, 413 2 of 14 reagent (2-chloro-1-methylpyridinium iodide) and numerous onium salt derivatives have been utilized in the synthesis of esters, thioesters, and amides through both inter-and intramolecular dehydrations of carboxylic acids [13] [14] [15] [16] [17] [18] [19] [20] . Notably, reagents in this class are generally effective for the synthesis of macrocyclic lactones [21] [22] [23] and lactams [24] [25] [26] [27] [28] , but also ring-strained β-lactones [29] and β-lactams [30,31] from acyclic precursors. Furthermore, ketene generation, C-N bond formation, rearrangements, hydroxyl activation, and a variety of other modes of reactivity, have been reported [13] [14] [15] . Results and Discussion Discovery of 2-Chloro-N-(1-ethoxyvinyl)pyridine-1-ium Triflate Our interest in the synthesis of antimicrobial N-alkylpyridinium alkaloids led us to explore the possibility of utilizing a formal [4 + 2]-cycloaddition approach from readily accessible N-vinyl amides, as shown in Scheme 1. In this exploratory reaction, we sought to examine the possibility that the embedded 2-aza-diene within the highly reactive N-vinyl iminium 2, produced via triflic anhydride-promoted amide activation [32] [33] [34] of N-vinylpyrrolidinone (NVP, 1), would exist long enough to react with ethoxyacetylene to provide pyridinium triflate 6 via a [4 + 2]-cycloaddition/elimination cascade [35, 36] . However, in initial experiments, the desired product 6 was not observed. This is likely because the transient dication intermediate 2, if generated, would rapidly convert to N-vinyl enamine 3, allowing for undesired side reactions to take place [37] . Instead, we observed that adduct 7, resulting from addition of 2-chloropyridine (5) to ketenium intermediate 4, was cleanly isolated from the crude product mixture in 10% yield. Molecules 2018, 23, x 2 of 14 Beyond their broad spectrum of biological activities, N-substituted pyridinium salts hold correspondingly broad potential as reagents in organic synthesis [4-6,10-12]. For example, Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) and numerous onium salt derivatives have been utilized in the synthesis of esters, thioesters, and amides through both inter-and intramolecular dehydrations of carboxylic acids [13] [14] [15] [16] [17] [18] [19] [20] . Notably, reagents in this class are generally effective for the synthesis of macrocyclic lactones [21] [22] [23] and lactams [24] [25] [26] [27] [28] , but also ring-strained β-lactones [29] and β-lactams [30,31] from acyclic precursors. Furthermore, ketene generation, C-N bond formation, rearrangements, hydroxyl activation, and a variety of other modes of reactivity, have been reported [13] [14] [15] . Results and Discussion Discovery of 2-Chloro-N-(1-ethoxyvinyl)pyridine-1-ium Triflate Our interest in the synthesis of antimicrobial N-alkylpyridinium alkaloids led us to explore the possibility of utilizing a formal [4 + 2]-cycloaddition approach from readily accessible N-vinyl amides, as shown in Scheme 1. In this exploratory reaction, we sought to examine the possibility that the embedded 2-aza-diene within the highly reactive N-vinyl iminium 2, produced via triflic anhydride-promoted amide activation [32] [33] [34] of N-vinylpyrrolidinone (NVP, 1), would exist long enough to react with ethoxyacetylene to provide pyridinium triflate 6 via a [4 + 2]cycloaddition/elimination cascade [35, 36] . However, in initial experiments, the desired product 6 was not observed. This is likely because the transient dication intermediate 2, if generated, would rapidly convert to N-vinyl enamine 3, allowing for undesired side reactions to take place [37] . Instead, we observed that adduct 7, resulting from addition of 2-chloropyridine (5) to ketenium intermediate 4, was cleanly isolated from the crude product mixture in 10% yield. 3.2.6. Synthesis of 1-(1-Ethoxyvinyl)-2-isopropoxypyridin-1-ium Trifluoromethanesulfonate (20) Using Method A with 2-fluoropyridine (172 µL, 2 mmol), compound 20 was obtained as an amorphous off-white solid (157 mg, 22%). 1 H-NMR (500 MHz, CDCl 3 ) δ 8.55 (ddd, J = 9.LRMS-ES+ m/z (relative intensity) 208.1 (C 12 H 18 NO 2 M+, 15); HRMS-ES+ (C 12 H 18 NO 2 ) calcd. 208.1338 (M+), found 208.1336; m.p.: 55-58 • C. Method D (Two-step protocol; Scheme 4). Freshly prepared 2-fluoro-1-(1-ethoxyvinyl)pyridine-1ium (19) (592 mg, 1.87 mmol) was dissolved in isopropanol (5 mL) and stirred for 18 h at room temperature. The resulting solution was concentrated in vacuo to provide a crude residue, which was purified by silica gel column chromatography with a 0-100% chloroform/isopropanol gradient,