Pyridinium N -heteroarylaminides: a brief study of the synthesis and reactivity under solvent-free mechanochemical conditions

The first example of a heterocyclic aromatic substitution by an N -ylide and the first examples of heteroaromatic halogenations in the presence of N -halosuccinimides using mechanochemical conditions are described.


Introduction
Over the past few decades, environmentally friendly processes based on the replacement of volatile organic solvents by other non-toxic and/or non-volatile solvents such as water, ionic liquids and supercritical fluids have attracted considerable attention. 1In this context, solvent-free conditions give rise to interesting alternatives. 2There are various approaches to carry out solvent-free reactions.For example, in solid-state reactions the use of ball mills leads to more reproducible processes whereas the mechanochemical approach, which is based on manually grinding together solid starting materials with a mortar and a pestle, provides the simplest and easiest method. 3Another attractive aspect is that in some cases these reactions are faster than the original solvent-based processes.
For several years our research program has to some extent focused on the study of pyridinium heteroaryl-stabilized aminides 1 (Figure 1). 4 These compounds have proven to be useful intermediates in heterocyclic synthesis, particularly in radical chemistry 5 and in Pd crosscoupling 6 and other metal-catalyzed methods. 7The presence of an electronegative substituent in the N-aminide nucleus can effectively assist the site-selective functionalization of the heterocyclic core and, as a result, halogenated species 2 (Figure 1) are our preferred starting materials for this kind of chemistry.Accordingly, some of our work has been dedicated to finding a set of appropriate conditions to obtain both N-aminides 1 and halogenated N-aminides 2 under clean, facile and non-polluting conditions and in synthetically useful yields.In this context, mechanochemical methods could provide an interesting alternative.In this paper we report our preliminary results on the preparation of stable heterocyclic betaine systems 1 and 2 using this methodology.To the best of our knowledge, this study represents the first example of a heterocyclic aromatic substitution by an N-ylide and the first example of heteroaromatic halogenations in the presence of N-halosuccinimides using mechanochemical conditions.

Results and Discussion
The classical synthesis of pyridinium N-aminides 1 is an adapted version of the method previously described by Beyer and Thieme 8 and it involves the reaction of Zincke salt (2,4dinitrophenylpyridinium chloride) 3 with the corresponding 2-heteroaryl hydrazine 4 in a typical ANRORC process to give the corresponding hydrazones.Acid catalysis then produces the pyridinium salts, which are transformed into the N-aminides 1 by treatment with base (Scheme 1, method A).Alternatively, an easy method can be used for various π-deficient heterocycles and it simply involves treating the commercially available N-aminopyridinium iodide 5 with the corresponding haloheteroaryls 6 (Y = Cl, Br) in the presence of base (Scheme 1, method B). 9,10 This method generates the pyridinium N-aminides 1 in a single step and is a suitable alternative to prepare a diverse range of these useful intermediates.More recently, 10 in an attempt to expand this simple methodology for the synthesis of pyridinium N-heteroarylaminides 1 and bearing in mind the palladium-promoted C-N bond formation developed by Buchwald and Hartwig, 11 we accomplished the formation of a C-N bond between several haloheterocycles 6 (Y = Cl, Br) and N-aminopyridinium iodide 5 using a palladium-catalyzed amination process (Scheme 1, method C).

Scheme 1
On considering the easier method (Method B, Scheme 1), we envisaged that the strategy for building up the N-aminide nucleus could involve a mechanochemical approach if it was possible to find suitable experimental conditions.Taking into account previous reports, 9 the nucleophilic substitution process could work well using chlorodiazines, in accordance with their more πdeficient character, whereas the reaction could not take place using simpler haloazines.Additionally, a nucleophilic substitution process could also work well in the presence of electron-withdrawing substituents (such as halogens), which would make the heterocyclic ring more π-deficient and facilitate attack by the nucleophile.Our initial results showed that a mixture of N-aminopyridinium iodide 5 and 6a (2,6-dichloropyrazine) can be converted into N-(6chloropyrazin-2-yl)pyridinium aminide 1a using potassium carbonate as the base.The best yield (70%) was obtained using a slight excess of the chloroheterocycle 6a (1.2 equiv) and excess base (3 equiv) at room temperature, with the solid starting materials ground manually with a mortar and pestle for 2-5 min (Entry 1, Table 1).Similar satisfactory results were obtained using 2,4dichloropyrimidine 6b as starting material, a reaction that yielded N-(2-chloropyrimidin-4yl)pyridinium aminide 1b in 82% yield without traces of the corresponding isomeric N-(4chloropyrimidin-2-yl)pyridinium aminide (Entry 2, Table 1).However, poor results were obtained starting from the monohalodiazines 3-chloro-6-phenylpyridazine 6c and 2chloroquinoxaline 6d, which have an additional π-system as a substituent or as a condensed ring.The corresponding N-(6-phenylpyridazin-3-yl)pyridinium aminide 1c and N-(quinoxalin-2yl)pyridinium aminide 1d were obtained in low yields (12 and 37%, respectively) (Entries 3 and 4, Table 1).Although all of the products have been reported previously with similar or better yields, 9,10 the method described here proved to be very convenient for multigram-scale synthesis, it avoids the use of solvent and it is considerably faster and cleaner than classical solvent-based methods.a Yields are given for isolated products.
On the other hand, halogenation reactions in the presence of N-halosuccinimidesone of the mildest sources of X +have grown in importance in modern organic synthesis.For example, Santi and co-workers 13a reported the use of N-halosuccinimides in organoselenium-catalyzed oxidative halogenations.Bengtsson and Almqvis 13b communicated the iodination of 2-pyridones in the presence of NIS.The aromatic halogenation of benzo-and dibenzocrown ethers in the presence of N-halosuccinimides and under mechanochemical activation has recently been studied. 14In a similar way, some of our work has concerned the use of different Nhalosuccinimides (NXS)a safe alternative to the use of molecular halogensin the preparation of a wide range of halogenated N-aminides. 15Taking into account the remarkable advantages of solvent-free approaches, we contemplated the possibility of attempting this kind of reaction under mechanochemical conditions.Initial experiments showed that a mixture of N-(pyridin-2-yl)pyridinium aminide 1e 4a,b (1 equiv) in the presence of N-bromosuccinimide (1.2 equiv) gave only poor yields of dibromoderivative 2a and monobromo-derivatives were not detected at all.Better results were obtained using a 2.2 molar excess of NBS and in this case 2a was obtained in 89% yield, which is an improvement on previously described yields 4a,4b,15 (Entry 1, Table 2).
Similar results were obtained using 1f, which contains an additional chloro-substituent in the 6-position, as the starting N-aminide 9 or when the reaction was attempted on the more π-deficient N-(6-chloropyrazin-2-yl)pyridinium aminide 1a, which gave dibromo derivatives 2b and 2c, respectively, as the only detectable products (Entries 2 and 3, Table 2).
As expected, when the reaction was carried out on N-(2-chloropyrimidin-4-yl)pyridinium aminide 1b, in which there is only one position susceptible to SEAr, in the presence of Nbromosuccinimide, a good yield of N-(5-bromo-2-chloropyrimidin-4-yl)pyridinium aminide 2d was obtained (Entry 4, Table 2).However, a similar process with N-(quinoxalin-2-yl)pyridinium aminide 1d gave only electrophilic substitution on the carbocyclic ring and no traces of 3-bromo derivative were detected, according to a pseudo-quinoline pattern (Entry 5, Table 2). 16odination in the presence of N-iodosuccinimide was also tested on the N-(pyrazin-2yl)pyridinium aminide 1g.4b,9 In this case only selective monoiodination at the 5-position was observed (Entry 6, Table 2) and all attempts to transform 2f into the diiodo-derivative were unsuccessful. 17

Conclusions
Differently substituted pyridinium N-heteroarylaminides have been prepared in one step under mechanochemical conditions.The reactions were carried out from N-aminopyridinium iodide and the corresponding heteroaryl chloride using potassium carbonate as the base.In a similar way, the regioselective halogenation of pyridinium N-heteroarylaminides was achieved in the presence of N-halosuccinimides.For both processes, the method proved to be very convenient for multigram-scale syntheses, 18 it avoids the use of solvent and is considerably faster and cleaner than classical solvent-based methods.

Experimental Section
General.Column chromatography was performed on silica gel (60 F254, 70-200 μm) as the stationary phase.All melting points are uncorrected.NMR spectra were obtained at 300 ( 1 H) and 75 ( 13 C) MHz.Chemical shifts are reported in ppm relative to tetramethylsilane.Compounds 1e, 4a,b 1f 9 and 1g 4b,9 were synthesized according to the previously reported procedures.The following compounds have been described previously: 1a, 9 1b, 9 1c, 9 1d 10 and 2a.4a,4b,15 General procedure for the preparation of pyridinium N-heteroarylaminides (1a-d) Potassium carbonate (0.153 g, 1.11 mmol), N-aminopyridinium iodide (0.083 g, 0.37 mmol) and the corresponding haloheterocycle (0.37 mmol) were added to a mortar.The mixture was ground with a pestle at room temperature and it acquired a yellow color.The reaction was completed in 2-5 min and the reaction mixture was dissolved in ethanol.The solution was filtered and the solvent was removed in vacuo.The product was purified by chromatography on silica gel using ethanol as eluent.Finally, the products were crystallized from the appropriate solvent and identified.

General procedure for the preparation of halo pyridinium N-(heteroaryl) aminides (2a-f)
The corresponding N-aminide 1 (1 mmol) and NXS (2.2 mmol for N-aminides 1a, 1d, 1e and 1f, and 1.1 mmol for N-aminides 1b and 1g) were added to a mortar.The mixture was ground with a pestle at room temperature.The reaction was completed in 2-5 min and the reaction mixture was dissolved in ethanol.The solvent was removed in vacuo and the product was purified by chromatography on silica gel using ethanol as eluent.Finally the compounds were crystallized from the appropriate solvent and identified.

Table 1 .
Synthesis of pyridinium N-heteroarylaminides by a mechanochemical approach

Table 2 .
Synthesis of halo pyridinium N-heteroarylaminides 2 by a mechanochemical approach from N-heteroarylaminides 1 a Yields are given for isolated products