The synthesis of 1,2,4-triazines bearing the residues of higher alcohols in the 5-position via the ipso-substitution of cyano group under the solvent-free conditions

E. S. Starnovskaya1, Ya. K. Shtaiz1, A. F. Khasanov1, I. S. Kovalev1, O. S. Taniya1, G. V. Zyryanov1,2, V. L. Rusinov1,2, O. N. Chupakhin1,2 1Ural Federal University, 19 Mira St., Ekaterinburg, 620002, Russia Tel./Fax: +7 (343) 375-45-01 2 Postovsky Institute of Organic Synthesis UB RAS, 22 Kovalevskaya St. / 20 Akademicheskaya St., Ekaterinburg, 620990, Russia Tel./Fax: +7 (343) 369-30-58, E-mail: dkopchuk@mail.


Results and discussion
5-Alkoxycontaining 1,2,4-triazines are of practical interest as receptors of gene expression [1] and inhibitors of enzymes of the MTH1-type in the treatment of cancer [2]. In order to obtain these compounds the following synthetic approaches were previously proposed: the alkylation of the hydroxyl group in the corresponding position of the 1,2,4-triazine [1,[3][4][5][6], and the ipso-substitution of a chlorine atom [7][8][9], trichloromethyl group [10], methylthio group [11] or fluorine atom [12]. The ipso-substitution of a cyanogroup deserves a special attention because 5-cyano-1,2,4-triazines are highly affordable compounds due to previously developed convenient method of obtaining them by using the direct nucleophilic substitution of hydrogen in the series of 1,2,4-triazine-4-oxides [13]. The different variations of the ipso-substitution of a cyanogroup are reported in a literature [14][15][16][17][18][19][20][21]. Typically, mineral or organic bases (potassium hydroxide, sodium alcoholate, sodium hydride, triethylamine) were used in this reaction. Additionally, there are examples of heating of the starting 5-cyano-1,2,4-triazines with excess of alcohols without additional activation (in particular, the use of such procedures was reported for the introduction of the residues of methanol, ethylene glycol and glycerin). In this article we proposed the modified method of introducing of the residues of higher alcohols into 1,2,4-triazines as a result of ipso-substitution of cyano group in the absence of solvents. It should be noted that fragments of such alcohols have never been introduced into 1,2,4-triazines before.
The initial 5-cyano-1,2,4-triazines 1 were obtained as described previously [15]. The substitution of cyano group in 1,2,4-triazines under the action of aromatic and aliphatic amines in heat was also reported by our group [22]. Based on the experimental data it was demonstrated that the residues of higher alcohols, such as decanol and tetradecanol, could be also successfully introduced into 1,2,4-triazines under the solvent-free conditions during the heating for 10 h at 150 °C. The reaction proceeds easily and with high yields of products 2.
Thus, in this paper we reported a new method for the modification of the C5position in 1,2,4-triazines by means of ipso-substitution of C5-cyanogroup by the residues of higher alcohols. And the obtained reaction products have never been previously reported in a literature.

Experimental
NMR 1 H spectra were recorded on the spectrometer «Bruker-Avance-400» (400 MHz), internal standard is SiMe 4 . The melting points were measured on the «Boetius» device. Mass spectra (type of ionization is electrospray) were recorded on the device of series «MicrOTOF-Q II» of «Bruker Daltonics» (Bremen, Germany). Elemental analyses were performed on CHN analyzer PE2400, series II by Perkin Elmer.

General procedure for the synthesis of 5-alkoxysubstituted 1,2,4-triazines 2.
A mixture of the corresponding 1,2,4-triazine-5-carbonitrile (0.4 mmol) and an appropriate alcohol (0.5 mmol) was stirred at 150 °C for 10 h under the argon. The resulting reaction mixture was cooled to room temperature, treated with hexane, and the precipitate formed was filtered off, washed with hexane and dried. Analytical samples were obtained by recrystallization from butanol.