Direct synthesis of 5-arylethynyl-1,2,4-triazines via direct CH-functionalization 104 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 3. 02 M. I. Savchuk, E. S. Starnovskaya, Y. K. Shtaitz, A. P. Krinochkin, D. S. Kopchuk, S. Santra, M. Rahman, G. V. Zyryanov, V. L. Rusinov, O. N. Chupakhin Chimica Techno Acta. 2020. Vol. 7, no. 3. P. 104–108. ISSN 2409–5613 M. I. Savchuk a, E. S. Starnovskaya ab, Y. K. Shtaitz a, A. P. Krinochkin ab, D. S. Kopchuk ab, S. Santraa, M. Rahmana, G. V. Zyryanov ab, V. L. Rusinov ab, O. N. Chupakhinab a Ural Federal University named after the first President of Russia B. N. Yeltsin, 620002, 19 Mira St., Ekaterinburg, Russia b I. Ya. Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 620990, 22/20 S. Kovalevskoy/Akademicheskaya St., Ekaterinburg, Russia *email: g.v.zyrianov@urfu.ru Direct synthesis of 5‑arylethynyl‑1,2,4‑triazines  via direct CH‑functionalization An efficient synthetic approach towards 5-arylethynyl-1,2,4-triazines via direct C-H-functionalization of 5-H-1,2,4-triazines in reaction with lithium acetylenes is reported. Keywords: C-H-Functionalization, 1,2,4-triazines; acetylenes lithium salts; 5-arylethynyl- 1,2,4-triazines Received: 05.08.2020. Accepted: 01.09.2020. Published: 07.10.2020. © M. I. Savchuk, E. S. Starnovskaya, Y. K. Shtaitz, A. P. Krinochkin, D. S. Kopchuk, S. Santra, M. Rahman, G. V. Zyryanov, V. L. Rusinov, O. N. Chupakhin, 2020 Introduction Heterocyclic acetylenes are wide- ly used in various heterocyclization reac- tions [1], especially via click reactions [2]. Acetylene spacers are presented in a num- ber of  conjugated heterocyclic chromo- phores [3]. Additionally, some heterocyclic acetylenes are known posses with biologi- cal activities, for instance as antihyperten- sive agents [4]. The object of study of this work — 5-ar- ylethynyl-1,2,4-triazines — are promising substrates for the preparation of various classes of compounds with unique applied properties. For example, by the transforma- tion of the 1,2,4-triazine ring into the pyri- dine one via the aza-Diels-Alder reaction with vatious dienophiles, the correspond- ing pyridines can be obtained, including 2,2’ — bipyridine ligands [4]. In addition, arylethynyl substituted 1,2,3-triazoles were obtained in the reaction of the cor- responding 3- (2-pyridyl)  — 1,2,4-tria- zines with aryne intermediates [5–6]. Also, by the chemical transformation of 5-ary- lethynyl the  corresponding 5-phenacyl- 1,2,4-triazines could be obtained [7–8], which in  turn can be transformed into 5-methyl-1,2,4-triazines [9]. Among the  reported methods for the synthesis of 5-arylethynyl-1,2,4-tria- zines, the use of the Sonogashira cross-cou- pling can be highlighted [10], and in this case 5-iodine or 5-chloro-1,2,4-triazines were used as reactants In addition, the di- rect introduction of an arylethynyl moiety via the C-H functionalization of 1,2,4-tria- zine-4-oxides in the reaction with the lithi- um salt of acetylene are described by using 105 deoxygenative aromatization pathway, and the benzoyl chloride was used as an acylat- ing agent [5,11]. The interaction of non-ac- tivated 1,2,4-triazines with the lithium salt of arylacetylene is also described, however, the corresponding 5-styryl-1,2,4-triazines were the main reaction products [12–13]. In this aspect, it should be noted the great- er availability of 1,2,4-triazines compare to 1,2,4-triazine-4-oxides; and the prepa- ration of ethynyl derivatives starting from 1,2,4-triazines looks more attractive. In this article, we wish to report an ef- ficient synthesis of 5-arylethynyl-1,2,4-tri- azines 1 via direct C-H-functionalization of 5-H-1,2,4-triazines 2 with lithium ary- lacetylenes. Experimental part 1H NMR spectra were recorded on a  Bruker Avance-400 spectrometer (400 MHz), the internal standard was SiMe4. Mass spectra (ionization type — electro- spray) were recorded on a MicrOTOF-Q II instrument from Bruker Daltonics (Bremen, Germany). Elemental analysis was per- formed on a Perkin Elmer PE 2400 II CHN analyzer. The starting 1,2,4-triazine 2 was obtained according to the described method [14]. A general procedure for the synthesis of of arylethynyl‑1,2,4‑triazines 1: A solution of n-BuLi in hexane (2.5 M, 0.8 ml) was added to a solution of the cor- responding arylacetylene (2 mmol) in dry THF (4 ml) in a Schlenk flask at a tempera- ture of –78 °C in an argon atmosphere, and the resulting mixture was stirred for 5 min. Then the  solution of  the  corresponding 1,2,4-triazine 1 (1.6 mmol) in dry toluene (35 ml) was added, and a minute later a so- lution of DDQ (305 mg, 1.34 mmol) in dry toluene (10 ml) was added. The resulting mixture was stirred for 3 h at 78 °C to room temperature. After that methanol (10 ml) was added, and the reaction mixture stirred for 5 min and the solvents were removed under reduced pressure. The resulting oily residue was purified by column chroma- tography (neutral alumina, eluent: dichlo- romethane) to afford the desired products. 3‑ (2‑Pyridyl) — 6‑phenyl‑5‑pheny‑ lethynyl‑1,2,4‑triazine (1а). Yield 565 mg (1.7 mmol, 85%). Rf 0.6. M.p. 142–144 °С. NMR 1H (CDCl3, δ, ppm): 7.37–7.41 (m, 2H, PhC≡C), 7.43–7.55 (m, 4H, PhC≡C, H-5 (py)), 7.59–7.63 ( m, 3H, Ph), 7.94– 7.99 (ddd, 1H, 3J 8.0, 8.0 Hz, 4J 2.0 Hz, H-4 (py)), 8.19–8.22 (m, 2H, Ph), 8.75 (dd, 1H, 3J 8.0 Hz, 4J 1.0 Hz, H-3 (py)), 8.96 (dd, 1H, 3J 4.8 Hz, 4J 2.0 Hz, H-6 (py)). 13C  NMR (CDCl3, δ, ppm): 86.5 (C-sp), 100.8 (C-sp), 120.8, 124.2, 125.7, 128.5, 128.7, 129.5, 130.7, 132.6, 133.9, 137.2, 142.6, 150.6, 152.4, 157.7, 160.7. ESI–MS, m/z: 335.13 (M + H)+. Found, %: C 78.82, H 4.01, N 16.55. C22H14N4. Calculated, %: C 79.02, H 4.22, N 16.76. 5  ‑ ((4‑Methoxyphenyl) ethynyl)  — 3‑ (pyridin‑2‑yl) — 6‑phenyl‑1,2,4‑tria‑ zine (1b). Yield 515 mg (1.41 mmol, 88%). NMR 1H (CDCl3, δ, ppm): 3.85 (m, 3H, OCH3), 6.89 (m, 2H, C6H4), 7.45–7.54 (m, 3H, C6H4, H-5 (py)), 7.55–7.64 (m, 3H, Ph), 7.95 (ddd, 1H, 3J 7.6 Hz, 7.6 Hz, 4J 1.6 Hz, H-4 (py)), 8.17–8.23 (m, 2H, Ph), 8.74 (d, 1H, 3J 8.0 Hz, H-3 (py)), 8.94 (d, 1H, 3J 4.8 Hz, H-6 (py)). ESI–MS, m/z: 365.14 (M + H)+. Found, %: C 75.70, H  4.30, N 15.25. C23H16N4O. Calculated,%: C 75.81, H 4.43, N 15.37. 106 Results and discussion The  previously proposed mechanism [14] for the  reaction of  1,2,4-triazines and lithium-acetylenes is  presented on the scheme 1. According to  the  mechanism, at the first stage, the corresponding σH-adduct A  is  formed, which further undergoes a  1,2-hydride shift affording the  forma- tion of  the  corresponding styryl sub- stituent. And the  treatment of  the  reac- tion mixture with methanol at  the  final stage leads to the products 3. Obviously, to block the pathway A for the reaction, the σH-adduct A need to be treated with and oxidant to  form 5-ethynyl-1,2,4-tri- azine 1, which no longer turn into 5-sty- ryl derivative 3 Indeed, it was found that the  addition of  an  oxidizing agent, such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), 10 minutes after the  initiation of the reaction between 1,2,4-triazine and the arylacetylene lithium salt allowed us to obtain the corresponding 5-phenylethy- nyl- 1,2,4-triazines 1 in up to 88% yields (way B), and they were isolated using col- umn chromatography. The structure of products 1 was con- firmed based on the data of NMR 1H, 13C spectroscopy, mass spectrometry, and el- emental analysis. Thus, in  the  13C NMR spectra, the signals of sp-hybrid carbon at- oms in the range of 86.5–100.8 ppm can be observed. The spectral data of compound 1а correspond to  those previously pub- lished during its synthesis by an alternative method [5]. Conclusions An efficient synthetic approach towards 5-arylethynyl-1,2,4-triazines via direct C- H-functionalization of 5-H-1,2,4-triazines in reaction with lithium-acetylenes was re- ported. This method could serve as a pos- sible Pd-free alternative to the Sonogashira cross-coupling. Acknowledgements This work was supported by the Russian Science Foundation (Grant # 20-13-00142) and Grants Council of the President of the Russian Federation (no. NSh-2700.2020.3). N N NPh Li Ar N N NPh Ar H N N NPh Ar MeOH Li+ BLi+ -MeOLi A H N N NPh Ar H H DDQ N N NPh Ar W ay A W ay B N N N NN 2 1a,b 3 Ar = Ph (a), 4-MeOC6H4 (b) Scheme 1. Mechanism of reaction of 5-H-1,2,4-triazines 2 with lithium-acetylenes 107 References 1. a) Heravi MM, Sadjadi S. Recent advances in the application of the Sonogashira method in the synthesis of heterocyclic compounds. Tetrahedron. 2009;65:7761– 7775. 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