Synthesis of 3-substituted pyridinium salts

A novel class of 3-substituted pyridinium salts have been synthesised in high yield by a convenient two-step procedure. A new synthetic pathway to 1-substituted benzimidazolium salts has been developed and the effects of the anionic component of the salts have been studied


Introduction
Compounds containing a pyridinium moiety attached to a heterocyclic system are important in natural product chemistry 1 and in organic synthesis 2, 3. Pyridinium salts have found use as acylating agents 4 , phase transfer catalysts 5 , biocides with a wide range of antimicrobial activity 6 , dyes 7 and cationic surfactants.The 1-alkylpyridinium salts, which are liquid at rt., so-called ionic liquids, are potential new solvents for synthesis and catalysis 8 .Several synthetic routes to pyridinium salts are known, but the most commonly used method is the Menschutkin reaction, the SN2 reaction of a pyridine derivative with an organic halide.Chloromethylalkyl ethers or sulphides are also reagents for the quaternization of the pyridine nitrogen.In these cases the reactions proceed via the SN1 mechanism [9][10][11] .
The present paper reports on a general and convenient route for the preparation of 3substituted pyridinium salts such as shown in Figure 1 by utilization of N-Mannich bases as starting materials.

Scheme 1
The chemotypes which have been prepared along with reaction times, yields and melting points are tabulated in Table 1.
The limitation of this procedure is that only two aldehydes, formaldehyde and benzaldehyde undergo reaction with benzimidazole and nicotinamide.

Y = CONH or NH; A = azole
The compounds were characterised by their 1H and 13C NMR spectra and by elemental analyses.The NH proton for 1a resonated at δ = 9.93 -9.89 as a triplet with a coupling constant in the range 5.6 Hz.The methine protons appeared in the spectrum as a doublet at δ = 5.83 -5.81 (J = 6 Hz).The chemical shift of the carbonyl carbon appeared at δ = 165.3.As expected, the absorption peak for the characteristic α carbon between the benzimidazole ring and the amide fall in the region of δ = 53 -48.Analogue 1c was prepared by treatment of 3-aminopyridine with formaldehyde and benzimidazole.The N-Mannich reagents, N-(1 H-benzotriazol-1-ylmethyl)-3-pyridinecarboxamide (1d) and 3-(benzotriazol-1-ylmethylamino)pyridine (1f), were easily prepared by the condensation of benzotriazole-formaldehyde with the appropriate amide or amine 14,15 .The 3-aminopyridine reacts with formaldehyde and benzotriazole at rt to give monosubstituted product 1f, previously prepared by the condensation of 3-aminopyridine with 1-(hydroxymethyl)benzotriazole 14 .
When the condensed product 1d was prepared directly from nicotinamide, formaldehyde and benzotriazole, the reaction conditions required were more vigorous due to the lower nucleophilicity of nicotinamide compared to 3-aminopyridine.
Analogue 1e was prepared from pyridine-3-carboxamide-benzaldehyde-benzotriazole.The reactions of benzotriazole was carried out in high yield with the regioselective formation of the N-1 isomer.In this condensation, azoles other than benzotriazole have been utilized (imidazole 16 , triazole 13 ).
The quaternization of a N-Mannich bases such as benzimidazoles 1a and 1c by chloromethylalkyl ether afforded two products 2 and 3 (Scheme 2).

ISSN 1551-7004
Page 892  ARKAT USA, Inc Scheme 2 The structure of the quaternazation product depends on the Y group in compounds 1a and 1c.The strong electron-withdrawing group (CONH) in the 3-position of the pyridine ring deactivates the nitrogen atom in pyridine.Chloromethylalkyl ether quaternarizes the N-3 of 1-substituted benzimidazole giving benzimidazolium chlorides 2 (Table 2).This study has shown that N-3 is Page 893  ARKAT USA, Inc nucleophilic enough to react with electrophiles.The pyridinium salts 3-6 were prepared by the reaction of N-Mannich bases 1c, 1d and 1f with chloromethylalkyl ethers.The reactions and the results are shown in Scheme 2 and Tables 3  and 4. a Solvent for recrystallization: MeOH/Me2CO (1:10) for 3a, 3b, H2O for 3c, MeOH/H2O (1:1) for 3c, 3d, H2O-4a, 4b, MeOH 4c-4i Symmetrically substituted bis(1-alkoxymethyl)pyridinium chlorides 4 were synthesised by trea-ting 1-alkoxymethyl-3-(1-benzimidazolmethylamino)pyridinium chloride 3 with chloromethyl-alkyl ether (Scheme 2).The formation of bispyridinium chloride is probably the result of the attack of chloromethylalkyl ether on the N-3 of benzimidazole ring to give an intermediate shown is Figure 2 which is unstable and quickly converted to bispyridinium chloride to replace the benzimidazole moiety.

Figure 2
The substrate 3 was converted into the same derivative 4 by heating with hydrochloric acid.
Benzimidazole is a good leaving group in N-(1 H-benzimidazolmethyl)-3pyridinecarboxamide 1a in basic and acidic solutions (Scheme 3).Hydrolysis is generally effected by heating with dilute hydrochloric acid.Treatment of compound 1a with alkoxides at rt, displaces the benzimidazole anion giving a symmetrical diamide.
The conversions of the chlorides to the Br, I, NO3, BrO3, ClO4, BF4, PF6 and SbF6 salts led to some which were hydrophobic.The larger -size anions changed the character of the salt.
In conclusion, a procedure has been developed for the preparation of 3-substituted pyridinium and 1-substituted benzimidazolium salts.The work-up procedures are very simple, the products are easily purified and the yields are high.

Scheme 3
Experimental Section General Procedures.Melting points were determined on a Kofter hot stage apparatus and are uncorrected.The 1H NMR spectra were recorded with a Varian Model XL 300 Spectrometer at 300 MHz with TMS as the standard.The 13C NMR spectra were recorded on the same instrument at 75 MHz.Elemental analyses was performed at the A. Mickiewicz University, Poznań.For all compounds 1-6 satisfactory microanalyses were obtained C ± 0.31, H ± 0.30 and N ± 0.28.Chloromethylalkyl ethers were prepared via the procedures, which were reported earlier 17 .
The salts obtained were characterised by their 1H and 13C NMR spectra and by elemental analyses.The 1H and 13C NMR chemical shifts are summarised in Tables 5-10.The chemical shifts of the protons are anion-dependent in equivalent concentrations.This effect is strong for protons in the Y group (H-N) and weaker for the benzimidazole or benzotriazole ring protons.The H-N chemical shift decreases in the following order Cl > NO3 > I, ClO4, PF6 > BF4.This phenomenon has been noticed previously in the imidazole ring protons in 1,3 dialkylimidazolium salts 18 .
General Procedure for the condensation of nicotinamide Nicotinamide (12.2 g, 0.1 mol), formaldehyde (3 g, 0.1 mol, paraformaldehyde -powder) and benzimidazole or benzotriazole (0.1 mol) were refluxed in toluene (200 mL) to which two drops of concd.sulphuric acid had been added.The water formed during the reaction was removed azeotropically by a Dean-Stark apparatus.The toluene was then removed under reduced pressure (60 oC/30 Torr) and the resulting solids were recrystallized.