Facile synthesis of bis(azolyl) derivatives in a superbasic meduim

Reaction of azoles (1,2,4-triazole, benzimidazole, bezotriazole) and dihalogenoderivatives of alkanes and oligoethyleneglycols in a superbasic KOHdimethylsulfoxide medium was used for the synthesis of bis(azolyl)alkanes and related compounds. The new method does not involve the use of toxic solvents and catalysts, does not require column chromatography for product separation and gives the target compounds in high yields.


Introduction
Organic compounds, containing several azole cycles -poly(azol-1-yl)alkanes (scorpionates) are chelating ligands forming complexes with most transition metals and some main group elements. Complexes with more than seventy elements are reported so far [1,2].
The chemistry of polydentate azole-containing ligands is still at the stage of a rapid development, which is clearly seen from a large number of reviews [3][4][5][6][7][8][9][10][11][12] and two separate books [13,14], published in recent years. The development of scorpionate chemistry is somewhat limited by the complex experimental procedures for their preparation, involving use of dry solvents, alkaline metals and their hydrides, expensive catalysts.

Experimental
NMR spectra were recorded on Bruker AV300 instrument operating at 300 MHz for 1 H and 75 MHz for 13 C. IR spectra were recorded on Nikolet 5700 (400-4000 cm -1 range) as KBr pellets.

Results and discussion
In case of benzotriazole alkylation it was found that the amount of potassium hydroxide greatly affects the product yield. Thus, decreasing the relative amount of KOH from 2 to 1.5 mole on one mole of starting benzotriazole results in product yield increase from 17 to 88-89 % at the same temperature (Table 1). Benzotriazole is more reactive in alkylation compared to pyrazole, which is probably explained by its greater acidity (ionization constants of benzotriazole and pyrazole in DMSO are pK a = 11.9 and pK a = 19.8 correspondingly [25]), leading to more effective heterocycle anion generation in the reaction mixture.
Since benzotriazole exists in two tautomeric forms, double alkylation reaction of benzotriazole gave three isomers with heterocycles substituted at nitrogen atoms 1 of 2 (Scheme 1, relative amounts of isomers are given, % mol. Yield of isomer mixture.
The signals in NMR 1H spectrum of product mixture 1a-1c overlap, so it was not possible to determine the product composition by NMR. Therefore, GC/MC method was used for the determination of relative amounts of isomers.
The mass-chromatogram of product mixture shows three peaks, molecular ion [M] + m/z = 250 corresponding to each of them ( Figure 1). For compound with the 6 smallest retention time, peak at m/z = 222, corresponding to nitrogen loss [M-N 2 ] + , is absent, and the molecular ion is fairly stable. In the mass-spectrum of the next compound (by retention time) peak with m/z = 222 appears and the intensity of molecular ion peak decreases. In the mass-spectrum of compound with the greatest retention time the peak of molecular ion decreases even more and the intensity of [M-N 2 ] + peak is about twice as much as in the spectrum of a previous product. The tentative fragmentation path of the molecular ion 1a is shown on scheme 2. Similar fragmentation pathway of 1-substituted benzotriazoles was proposed in paper [26].
The results obtained suggest that the first compound, incapable of nitrogen loss Relative amounts of the isomers calculated from the signal integral intensities are shown on Scheme 1. As one can see, the ratio is close to statistical, therefore, alkylation of benzotriazole cycle by 1,3-dibromopropane at positions 1 and 2 proceeds with approximately equal probability.
The proposed approach was employed here for the analysis of the regioselectivity of benzotriazole alkylation by dibromomethane in a superbasic medium.
The members of a 2 +2ab+b 2 sum are proportional to parts of the isomers A, B and C in product mixture. The sum of squared deviations of these parts form sum members is: Taking into account that a+b=1, we get a one-argument function, minimization of which gives coefficients a and b, characterizing the relative activity of two nucleophilic centers in benzotriazolate-anion.
When a[0;1] this function has only one minimum at a=0.842, which gives the relative activity of two nucleophilic centers of 84:16. It should be noted that this ratio characterizes the average reactivity of benzotriazolate anion in two stages, since this reactivity is influenced not only by the electronic factors, but also by steric factors which are different for the substitution of the first and the second halogen atoms, as well for different linker length.
It can be assumed that the coordination compounds of ligands 1a-1c demonstrate different stability. This would allow to isolate the isomer forming the most stable complexes. It was found, that when the mixture of isomers 1a-1c is The structure of bis(benzotriazol-1-yl)methane isomers was additionally studied by X-Ray diffraction, the results are reported elsewhere [28].
Alkylation of benzimidazole and 1,2,4-triazole proceeds smoothly at 80 °C and double excess of KOH (Scheme 3). Table 2 lists the formulas, yields and melting points of synthesized products together with literature data.

Conclusion
In summary, the method proposed here for the synthesis of bis(azolyl)alkanes and related compounds has several advantages compared to the methods described in literature -only non-toxic DMSO is used as solvent, there is no need for the use of expensive phase transfer catalysts and other reagents requiring special handling, such as sodium hydride and alkaline metals. The methods are easily scalable to multigram quantities.