The rearrangement of 3-nitropyridinium salts to 3-nitropyrroles

The rearrangement of 3-benzoylamino-5-nitropyridinium quaternary salts by ethanolic methylamine results in the formation of 2-acyl-4-nitropyrroles.

The necessary pyridinium salts 3a-e were obtained by alkylation of pyridines 2a-e with dimethyl sulfate and methyl fluorosulfonate.Hygroscopic pyridinium methyl sulfates were transformed into the less-soluble pyridinium perchlorates 3 by replacement of the methyl sulfate anion to perchlorate (Table 2).
The rearrangement of pyridinium salts 3 under the action of methylamine solution in ethanol results in 2-acylpyrroles 4 as the main product of reaction.The side (minor) rearrangement products are substituted nitrobenzenes 5, which were isolated in trace amounts (Table 3).
The rearrangement of pyridinium salts 3 to pyrroles 4 occurs by addition of methylamine at position 2 of the pyridinium salt 3 to form a 1,2-    The rearrangement of 2,4-diphenyl-5-nitropyridinium salt 3e in the same conditions is accompanied by strong reaction mixture resinification and results in only benzene 5e formation, pyrrole 4e was not found in the reaction mixture.It is likely to be connected with influence of steric factors, determined by a large difference in size of substituents (Ph>>Me).The rotation around C3-C4 bond in open form В (R 2 = R 3 = Ph) necessary to close pyrrole ring does not occur (Table 3, Scheme 1).
It was established on the example of 3-benzoylamino-5-nitro-4-phenyl-2,6-dimethyl pyridinium salt 3d, that in ethanolic methylamine solution the rearrangement proceeds with maximum pyrrole 4d yield.The replacement of ethanolic methylamine solution by aqueous solution significantly decreases nitropyrrole 4d yield and increases the proportion of methylaminobiphenyl 5d.Further decrease of pyrrole 4d yield and increase in that of methylaminobiphenyl 5d occurs when the reaction proceeds under the action of aqueous dimethylamine solution.The rearrangement of salt 3d in aqueous ethanolic NaOH solution occurs specifically with formation of only methylaminobiphenyl 5d; pyrrole 4d is not formed under these conditions (Table 4).It is known that the basicity of methylamine is less in ethanol (pКа of conjugate acid is 9.58) than in water (pКа is 10.66). 40,41Therefore, the less basic ethanolic methylamine deprotonates only the more acidic NH proton of the benzamido group and this results in formation of pyrrole 4d (Scheme 2).The more basic methylamine and dimethylamine aqueous solutions (pКа 10.73) deprotonate the NH group and remove proton from the methyl group of intermediate F that participates in intramolecular crotonic condensation.Cyclization of the dianion F occurs selectively with formation of the thermodynamically favorable methylaminobiphenyl 5d as the main product (Table 4 and Scheme 2). 37

Conclusions
A new approach to 2-acyl-4-nitropyrroles synthesis is developed and the optimum reaction conditions found.The rearrangement proceeds by breaking a С-N bond in pyridine and recyclization with pyridine ring contraction.The source of the pyrrole nitrogen is the nitrogen atom of the exocyclic benzoylamino group of the pyridinium salt.The rearrangement of 5-amino-N-methyl(aryl)isoquinolinium salts to 4-formylindoles can be the logical continuation and extension of this reaction.

Experimental Section
General. 1 H NMR spectra were recorded on a Bruker Avance DRX-400 (400 MHz) in CDCl3 and DMSO-d6, internal standard was the residual protons of the solvent (CDCl3  7.25 and DMSO-d6  2.50 ppm). 13C NMR spectra were recorded on a Bruker DRX-400 (100 MHz) spectrometer with DMSO-d6 ( C 39.50 ppm) and CDCl3 ( C 77.00 ppm) as internal standard.The IR spectra were obtained on a Simex FT-801 instrument with an attachment for a single broken internal reflection.Elemental analysis was carried out on a Perkin-Elmer CHN Analyzer.Column chromatography was carried out using Merck silica gel (60A, 0.060-0.200mm).The reaction progress and purity of the synthesized compounds was monitored by TLC method on Silufol UV-254 plates.The reagents and solvents used in this work were obtained from Aldrich and Fluka and were used without further purification.The substrates of 3-aminopyridines 1a-e were prepared according to known procedures. 39eneral procedure for the synthesis of 3-(benzoylamino)-5-nitropyridines (2a-e).Benzoyl chloride 1.08 g (7.7 mmol) was added dropwise to solution of 3-aminopyridine 1a-e (7 mmol) in absolute pyridine (5 mL) at 0 °C.The mixture was stirred for 10 min at 0 °C and then for 2 h at room temperature.After that, absolute ethanol (1.5 mL) was added to the mixture and it was stirred for 10 min.The reaction mixture was diluted with cooled water and the precipitate was filtered.Pyridines 2a-e were recrystallized from 95% ethanol.General procedure for the synthesis of N-methylpyridinium salts ( 3a,b,d,e).The mixture of pyridine 2a,b,d,e (5 mmol) and Me2SO4 1.4 mL (15 mmol) was heated (the heating conditions specified below).Then, mixture was chilled and washed with dry ether (3 × 10 mL) and the ether was removed by decantation.All the residues except non-hygroscopic 3-(benzoylamino)pyridinium methylsulfate 3a were dissolved in H2O (5 mL) and saturated aqueous solution of NaClO4 (5.3 mmol) was added.Finally, the pyridinium salts 3a,b,d,e were filtered, dried and recrystallized from ethanol.

3-(Benzoylamino)-1,6-dimethyl-5-nitro-2-phenylpyridinium fluorosulfonate (3c).
The solution of MeSO3F (15 mol) in chlorobenzene (3 mL) was added dropwise to stirred solution of pyridine 2c (5 mmol) in chlorobenzene (15 mL) at 0 °C.The mixture was stirred for 30 min at 0 °C and than, for 5 days at room temperature.After that, the mixture was diluted with diethyl ether.The precipitate was filtered and recrystallized from ethanol.The colorless crystals were obtained in 90% yield, mp 209-210 °С. 1 Method A).The 30% solution of the methylamine in ethanol (20 mL) was added to a solution of the corresponding salt 3a-e (1 mmol) in DMF (1 mL) and the mixture stirred for 72 h at room temperature.The solvent was evaporated under reduced pressure, than, the separation of nitropyrroles 4a-e and nitroanilines 5a-e was carried out by column chromatography on silica gel.The products were recrystallized from ethanol.

Supplementary Material
The original data of NMR spectra of all new compounds are supplied.
dihydropyridine A, followed by its isomerization to the open form В. Bond rotation and cyclization of open form C to pyrrole ring is the result of interaction of amide anion and electrophilic carbon atom of Schiff base (nitrogen analogue of a carbonyl group).The rotation around C3-C4 bond, which results in spatial closure of nucleophilic and electrophilic centers in open form C, precedes the stage of formation C-N bond in pyrrole (Scheme 1).

Scheme 1 .
Scheme 1. Possible mechanism for the formation of nitropyrroles 4.

Table 3 .
Rearrangement of N-methylpyridinium salts 3 by 30% MeNH2 solution in ethanol a b Isolated and purified compounds.c Not determined.

Table 4 .
Rearrangement of N-methylpyridinium salt 3d by 30% MeNH2 solution in ethanol a (Method A), 40% aqueous solution of MeNH2 b (Method B), 40% aqueous solution of Me2NH c (Method C) and 10% aqueous solution of NaOH d (Method D)