A convenient synthetic approach to 5-(het)arylhydrazine substituted 1,2,4-triazines 204 A convenient synthetic approach to 5-(het)arylhydrazine substituted 1,2,4-triazines A. P. Krinochkinab, M. R. Gudaa, A. Rammohana, D. S. Kopchukab, G. V. Zyryanovab*, V. L. Rusinov ab, O. N. Chupakhinab a Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st., Ekaterinburg, 620002, Russian Federation bI.Ya. Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya st., Ekaterinburg, 620990, Russian Federation *email: g.v.zyrianov@urfu.ru Abstract. A convenient synthesis of 1,2,4-triazines bearing the moieties of (hetero) arylhydrazines at the position of C5 of the 1,2,4-triazine core is reported. Keywords: 1,2,4-triazines; (hetero)arylhydrazines; 5-cyano-1,2,4-triazines; ipso-substitution Received: 09.09.2020. Accepted: 20.12.2020. Published:30.12.2020. © Krinochkin A. P., Guda M. R., A. Rammohan, Kopchuk D. S., Zyryanov G. V., Rusinov V. L., Chupakhin O. N., 2020 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 4. 12 Krinochkin A. P., Guda M. R., A. Rammohan, Kopchuk D. S., Zyryanov G. V., Rusinov V. L., Chupakhin O. N. Chimica Techno Acta. 2020. Vol. 7, no. 4. P. 204–208. ISSN 2409–5613 Introduction 1,2,4-Triazines with moieties of (hetero)arylhydrazines at С5 position are of  interest as  substrates for further heterocyclizations for the  synthesis of different condensed triazines, e.g., 2H- pyrazolo[3,4-e][1,2,4]triazin-7(6H)  — ones, 2,6-dihydro-[1,2,4]triazino[5,6-d] [1,2,3]triazin-4-amines [1] or 2,6-dihy- dro-[1,2,4]triazino[6,5-e][1,2,4]triazines [2]. As for the methods for the synthesis of  similar compounds it was previously proposed ipso-substitution of  (methyl) sulfanyl group by arylhydrazine [2]. Also, there is  a  number of  heterocyclizations of 1,2,4-triazine ring with the desired sub- stituent at C5 position [1, 3, 4]. In addition, the opening of the condensed furan ring at the positions of C5 and C6 of the triazine ring is possible under the action of arylhy- drazine [5]. At the same time, a known approach to  the  preparation of  various 1,2,4-tria- zines with the  residues of  various nu- cleophiles at  position C5 is  the  ipso- substitution of the C5-cyano group. This is due to the easy availability of 5-cyano- 1,2,4-triazines obtained via the  nucleo- philic substitution of  hydrogen process [6]. Thus, the possibility of the substitu- tion of  the  C5-cyano group by  the  resi- dues of such nucleophiles as alcohols [7–9], amines [7,10,11], anilines [12–14], lithium- carboranes [15], various CH acid residues [16, 17], hydrazides of carboxylic acids [18, 19] etc. was demonstrated earlier. In this article we wish to  report the  synthesis of 1,2,4-triaizines bearing (hetero)arylhy- drazine moieties at position C5 by means of  ipso-substitution of  C5-cyanogroup in 1,2,4-triazines under the action of (het) arylhydrazines. 205 Experimental part NMR 1H and 19F spectra were re- corded on a  Bruker Avance-400 spec- trometer (400  MHz), the  internal standard was correspondingly SiMe4 or CFCl3. Mass-spectra (ionization type  — electrospray) were recorded on a MicrOTOF-Q II instrument from Bruker Daltonics (Bremen, Germany). Elemental analysis was performed on a Perkin Elmer PE 2400 II CHN analyzer. The  starting 5-cyano-1,2,4-triazines 1 were obtained according to the described method [8]. A general procedure for the synthesis of  5-(het)arylarylhydrazinyl substi- tuted 1,2,4-triazines 2 The mixture of corresponding 5-cyano- 1,2,4-triazine 1 (1 mmol) and the corre- sponding (het)arylhydrazine (1.05 mmol) was stirred at  150  °C for 8  h in  argon atmosphere. After cooling down the ob- tained residue was crashed and dissolved in chloroform (5-10mL). The final prod- ucts were isolated by flash chromatography on SiO2 using chloroform as eluent. 2-(2-(3,6-Diphenyl-1,2,4-triazin- 5-yl)hydrazinyl)benzo[d]thiazole (2a). Yield 305 mg (0.77 mmol, 77%). NMR 1H (DMSO-d6, δ, ppm): 2.42 (s, 3H, Me), 7.02– 7.09 and 7.22–7.28 (both m, 1H, H-5,6 (benzothiazole)), 7.43–7.47 (m, 1H, H-7 (benzothiazole)), 7.50–7.60 (m, 5H, Ph), 7.61–7.65 (m, 1H, Ph), 7.66–7.71 (m, 1H, H-4 (benzothiazole)), 8.16–8.22 (m, 2H, Ph), 8.35–8.40 (m, 2H, Ph), 10.84 (s, 1H, NHNH), 13.02 (s, 1H, NHNH). ESI–MS, m/z: 397.12 (M+H)+. 2-(2-(3-(4-Fluorophenyl)-6-(p-tolyl)- 1,2,4-triazin-5-yl)hydrazinyl)benzo[d] thiazole (2b). Yield 310 mg (0.72 mmol, 72%). NMR 1H (DMSO-d6, δ, ppm): 2.42 (s, 3H, Me), 7.07 and 7.28 (both ddd, 3J 7.6, 7.6 Hz, 4J 1.2 Hz, H-5,6 (benzothiazole)), 7.33–7.36 (m, 2H, CH3C6H4), 7.40–7.45 (m, 2H, C6H4F), 7.45–7.48 (m, 1H, H-7 (ben- zothiazole)), 7.77–7.80 (m, 1H, H-4 (ben- zothiazole)), 8.03–8.06 (m, 2H, CH3C6H4), 8.49–8.54 (m, 2H, C6H4F), 11.33 (s, 1H, NHNH), 13.07 (s, 1H, NHNH). ESI–MS, m/z: 429.13 (M+H)+. 5-(2-(4-Fluorophenyl)hydra zinyl)- 3,6-di-p-tolyl-1,2,4-triazine (2c). Yield 310  mg (0.80 mmol, 80%). NMR 1H (CDCl3, δ, ppm): 2.43 (s, 3H, Me), 2.45 (s, 3H, Me), 6.90–6.96 (m, 2H, C6H4F), 6.98–7.02 (m, 2H, C6H4F), 7.25–7.28 (m, 2H, CH3C6H4), 7.25–7.28 (m, 2H, CH3C6H4), 7.29–7.33 (m, 2H, CH3C6H4), 7.75–7.78 (m, 2H, CH3C6H4), 7.96–8.00 (m, 2H, CH3C6H4), 8.79 (s, 1H, NHNH), 9.22 (s, 1H, NHNH). NMR 19F (CDCl3, δ, ppm): –126.51 (s, 1F). ESI–MS, m/z: 386.18 (M+H)+. 5-(2-Phenylhydrazinyl)-3,6-di-p- tolyl-1,2,4-triazine (2d). Yield 280  mg (0.76 mmol, 76%). NMR 1H (DMSO-d6, δ, ppm): 2.44 (s, 3H, Me), 2.46 (s, 3H, Me), 6.61–6.67 (m, 1H, Ph), 7.03–7.08 (m, 2H, Ph), 7.10–7.16 (m, 2H, Ph), 7.24–7.30 (m, 2H, CH3C6H4), 7.32–7.37 (m, 2H, CH3C6H4), 8.00–8.05 (m, 2H, CH3C6H4), 8.09–8.13 (m, 2H, CH3C6H4), 9.10 (s, 1H, NHNH), 12.34 (s, 1H, NHNH). ESI–MS, m/z: 368.19 (M+H)+. Results and discussion The starting 5-cyano-1,2,4-triazines 1 were synthesized as  described in  litera- ture [8]. Ipso-substitution reaction was carried out under the solvent-free condi- tions, as reported earlier for anilines and hydrazides [12, 18] (Scheme 1). The structure of the obtained products 2 was confirmed by using NMR 1Н, mass- 206 spectrometry and elemental analysis. Thus, NMR 1H spectra of compound 2 contains two characteristic broadened singlets for N-H-protons in  the  area of  8.79–13.07 ppm, signals of protons of the substituents at the positions of С3 and С6 of the triazine moiety, as  well as  the  signals of  protons of (hetero)aromatic substituents of hydra- zines. It is worth to mention that, di(het)aryl hydrazine moieties are found in  many natural and synthetic biologically active compounds [20–22]. Therefore, further studies are needed to evaluate the reactiv- ity, biological activity and chelating proper- ties of the obtained products 2. Conclusions In conclusion, we have reported here- in a convenient method for the synthesis of  3,6-disubstituted 1,2,4-triazines bear- ing moieties (het)arylhydrazine residues at the position of C5 of the triazine core by  means of  ipso-substitution of  cyano- group in 1,2,4-triazine-5-carbonitriles by (het)arylhydrazines under the solvent-free conditions. References 1. 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