Two mutually complementary synthetic approaches towards 3 ‐ substituted 3 , 4 ‐ disubstituted and 1 ‐ ( 2 ‐ pyridyl ) ‐ substituted isoquinolines

I. L. Nikonov, D. S. Kopchuk, A. F. Khasanov, A. P. Krinochkin, E. S. Starnovskaya, Ya. K. Shtaiz, M. I Savchuk, O. S. Tanya, G. V. Zyryanov, V. L. Rusinov, O. N. Chupakhin Ural Federal University, 19 Mira St., Ekaterinburg 620002, Russian Federation I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, 22 Kovalevskaya St. / 20 Akademicheskaya St., Ekaterinburg 620990, Russian Federation E-mail: dkopchuk@mail.ru


Results and Discussion
Aryne intermediates, generated in situ, are currently attracting more and more attention from the point of view of their use in organic synthesis, since practically useful products of various purposes can be obtained [1][2][3].Recently, we have demonstrated the possibilities of their successful use in reactions with substituted 1,2,4-triazines for obtaining both the expected aza-Diels-Alder reaction products, namely the corresponding isoquinolines, and the domino transformations, for example, 10-(1H-1,2,3-triazol-1-yl) pyrido [1,2-a] indoles.The direction of the reaction depends on the nature of the 1,2,4-triazines (or aryns) introduced into the composition of the substituents [4].
This article analyzes the two synthetic approaches we have developed for the synthesis of 1-(2-pyridyl) isoquinolines with different substituents in the C3 and C4 positions, which are of interest, in particular, as ligands for transition metal cations [5], as well as from the point of view of creating OLED [6].
Thus, the reaction of 3-(2-pyridyl) -1,2,4-triazines 1a, having an aromatic substituent or a hydrogen atom at the C5 position, with aryne results in the corresponding pyrido [1,2-a] indoles 2 [7] (scheme 1), while the synthesis of target 1-(2-pyridyl) isoquinolines 3a in this way is impossible.To solve this problem, we developed an alternative synthetic approach, which was based on the use of 3-(2-pyridyl)-1,2,4-triazines 1 as starting compounds.The approach involves the preparation of 5,6,7,8-tetrahydroisoquinolines 4a as a result of the reaction of aza-Diels-Alder (Boger) with enamine followed by oxidative aromatization of the isoquinoline system [8].1-Morpholinocyclohexene was used as a dienophile for the first stage.Subsequent aromatization using DDQ as an oxidizing agent made it possible to successfully synthesize isoquinolines 3a.
It should be noted that in the reaction of 3-(2-pyridyl)-1,2,4-triazine-5-carbonitriles 1b with arynes, the corresponding isoquinolines 3b were also obtained as main products, whereas the products of domino transformation were the minor products (the yield is not more than 3 %) [9].
We also investigated the possibility of obtaining isoquinolines 3b as a result of two-stage synthesis through the preparation of tetrahydroisoquinolines 4b.The first step was performed by the same procedure as in the case of synthesis 4a, and afforded the compound 4b.However, subsequent aromatization of tetrahydrocyanoisoquinoline under various conditions, such as boiling in o-xylene or 4-chlorotoluene with oxidants, such as DDQ or chloranil, as well as prolonged boiling in the same high-boiling solvents in the pre sence of Pd / C did not lead to the formation of the desired isoquinolines 3b.In all cases the initial tetrahydroisoquinoline 4b was isolated.Thus, the application of this method is not acceptable for the obtaining the target 3-cyanoisoquinolines 3b.
Thus, it was demonstrated that two mutually complementary synthetic methodologies can be used to synthesize 3-aryl, 3,4-diaryl-, as well as 3-cyano-1-(2-pyridyl)isoquinolines.Thus, in the case of R = CN (Scheme 1), the synthesis using aryne intermediates makes it possible to efficiently obtain the corresponding isoquinolines 3b, while the method based of the preparation tetrahydroisoquinolines 4b does not allow this because of the impossibility of subsequent aromatization by using the common methods.At the same time, in the case of R = H or Ar, the opposite situation is observed: the synthesis of isoquinolines 3a is possible with the use of a two-step pathway by using the corresponding enam-ine, and in the case of using aryl intermediates, the reaction leads mainly to rearrangement products 2.

Experimental
NMR 1 H and 13 C 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 PE 2400, series II by Perkin Elmer.