N-benzylpyridinium Salts Research Articles

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a "Bio-Oxidizable" Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation.

With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.

Pyridinium oxidations of benzyl alcohol under microwave-assisted retro-ene conditions

Benzyl alcohol is oxidized to benzaldehyde when heated in sulfolane in the presence of N-benzylnicotinamide and N-benzylpyridinium salts. The oxidation is accelerated in the presence microwaves. Oxidations with related pyridiniums suggest that these oxidations could occur via retro-ene reactions.

Catalytic Enantioselective Addition of Indoles to Activated N-Benzylpyridinium Salts: Nucleophilic Dearomatization of Pyridines with Unusual C-4 Regioselectivity

The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on N-acylpyridinium salts, give addition to the C-2/C-6 of the pyridine nucleus, rendering 1,2-/1,6-dihydropyridines. Herein, we present an alternative approach to this type of dearomatization reaction, employing activated N-benzylpyridinium salts in combination with a bifunctional organic catalyst. Optically active 1,4-dihydropyridines resulting from the addition of the nucleophile (indole) to the C-4 of the pyridine nucleus are obtained as major products, rendering this method for nucleophilic dearomatization of pyridines complementary to previous approaches.

ChemInform Abstract: N-Benzylpyridinium Salts as New Useful Catalysts for Transformation of Epoxides (I) to Cyclic Acetals (III), Orthoesters (Va), (Vc), and Orthocarbonates (Vb).

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Pyridinium salts and ylides as partial structures of photoresponsive Merrifield resins

Merrifield resin was treated with 4,4′-bipyridine and 2,4′-bipyridine, respectively, to give photochromic materials. On exposure to light, reversible color changes are observable. These resins also serve as indicators because reversible color changes are observable on addition of bases, which deprotonate the benzylic position of the N-benzylpyridinium salts to ylides. These can be detected spectroscopically and by trapping reactions on monomeric model compounds. EPR and HYSCORE measurements in combination with DFT calculations prove that radical species are formed in either case. Evidence is found that the carbanionic centers of the ylide partial structures serve as electron donators in these reversible color changes, thus setting them apart from known photochromic materials.

Quaternary ammonium salts as useful cationic initiators. 6. Synthesis, activity, and thermal latency of N-benzylpyridinium salts and the role of the pyridine moiety

N-Benzyl-, N-(1-phenethyl)-, and N-(p-methoxybenzyl)-o-cyanopyridinium hexafluoroantimonate (2a, 2b, and 2c, respectively). N-(p-Methoxybenzyl)-m-(methoxycarbonyl) pyridinium, N-benzyl-p-methylpyridinium, and N-benzyl-o-methylpyridinium hexafluoroantimonate were prepared, and their initiator activities were evaluated similarly. The o-cyanopyridinium salts 2 showed much higher activity than the corresponding p-cyanopyridium salts in the cationic polymerization of glycidyl phenyl ether. The activity change was attributed to the electronic and steric effect of the o-cyano group of pyridine. A plausible mechanism is discussed, which involved competitive attack of monomer and liberated free pyridine group on the cationic propagating end

Kinetics and mechanisms of nucleophilic displacements with heterocycles as leaving groups. Part 25. X-Ray structure determinations, crystallographic evidence for steric crowding, and correlation with acceleration of rates

X-Ray crystallographic structures are determined for seven N-benzylpyridinium salts including compounds possessing free, five-ring fused, and six-ring fused α-phenyl groups. Significant bond lengths, non-bonding distances, torsional and interplanar angles are determined and compared for the eight structures (the triphenyl derivative was found in two crystal environments). The results show steric overcrowding to an extent that parallels the kinetic displacement rates. However, the steric strain existing in all these molecules is relieved to different extents by different distortions in the different molecules. Nevertheless, crystallographic interatomic distances and angles are shown to be of potential utility in determining the type of mechanistic changes to be undergone, provided the appropriate parameters are selected.

The synthesis of some highly strained pyrylium and N-benzylpyridinium salts and kinetics of their reactions with piperidine

5,8-Dimethyl-1-tetralone (11) yields the hindered pyrylium salts (12)—(14), which give the corresponding pyridines and pyridinium salts with ammonia and amines. Chroman-4-one affords the oxoniaphenanthrene perchlorate (17). The additional steric hindrance from the C-methyl groups in (28) and (16) decreases the rate of SN2 displacement. 2,4-Diphenylbenzo[h]chromenylium (7) and 5,6-dihydro-7-phenyldi-benzoxanthylium tetrafluoroborates (8) do not give the corresponding pyridinium salts with aliphatic amines.Benzo[f]chromanone with αβ-unsaturated ketones yielded tetracyclic pyridinium salts (33) and (34). Acenaphthenone derived pyrylium salts (39), (40), and (46), were prepared from benzylideneacetophenone, styryl t-butyl ketone, and benzo[f]chromanone. Kinetic measurements on derived N-benzylpyridinium salts demonstrated that the αβ-fusion of an acenaphthene ring decreased the tendency of a pyridine to act as a leaving group compared to the corresponding 2-phenylpyridine.