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-Hfunctionalization of 5-H-1,2,4-triazines in reaction with lithium acetylenes is reported.


Introduction
Heterocyclic acetylenes are widely used in various heterocyclization reactions [1], especially via click reactions [2]. Acetylene spacers are presented in a number of conjugated heterocyclic chromophores [3]. Additionally, some heterocyclic acetylenes are known posses with biological activities, for instance as antihypertensive agents [4].
Among the reported methods for the synthesis of 5-arylethynyl-1,2,4-triazines, the use of the Sonogashira cross-coupling can be highlighted [10], and in this case 5-iodine or 5-chloro-1,2,4triazines were used as reactants In addition, the direct introduction of an arylethynyl moiety via the C-H functionalization of 1,2,4-triazine-4-oxides in the reaction with the lithium salt of acetylene are described by using deoxygenative aromatization pathway, and the benzoyl chloride was used as an acylating agent [5,11]. The interaction of non-activated 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 greater availability of 1,2,4-triazines compare to 1,2,4-triazine-4-oxides; and the preparation of ethynyl derivatives starting from 1,2,4triazines looks more attractive.

Experimental part
1 H NMR spectra were recorded on a Bruker Avance-400 spectrometer (400 MHz), the internal standard was SiMe4. 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 1,2,4-triazine 2 was obtained according to the described method [14].

Results and discussion
The previously proposed mechanism [14] for the reaction of 1,2,4-triazines and lithiumacetylenes is presented on the scheme 1.
Scheme 1. Mechanism of reaction of 5-H-1,2,4-triazines 2 with lithium-acetylenes According to the mechanism, at the first stage, the corresponding σ H -adduct A is formed, which further undergoes a 1,2-hydride shift affording the formation of the corresponding styryl substituent. And the treatment of the reaction 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-triazine 1, which no longer turn into 5-styryl derivative 3 Indeed, it was found that the addition of an oxidizing agent, such as 2,3-dichloro-5,6dicyanobenzoquinone (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-phenylethynyl-1,2,4triazines 1 in up to 88% yields (way B), and they were isolated using column chromatography.
The structure of products 1 was confirmed based on the data of NMR 1 H, 13 C spectroscopy, mass spectrometry, and elemental analysis. Thus, in the 13 C NMR spectra, the signals of sp-hybrid carbon atoms in the range of 86.5-100.8 ppm can be observed. The spectral data of compound 1а correspond to those previously published during its synthesis by an alternative method [5].