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


150

I. L. Nikonov1,2, D. S. Kopchuk1,2, A. F. Khasanov1,2, 
A. P. Krinochkin1,2, E. S. Starnovskaya1, Ya. K. Shtaiz1, 

M. I Savchuk1, O. S. Tanya1, G. V. Zyryanov1,2,  
V. L. Rusinov1,2, O. N. Chupakhin1,2

1Ural Federal University,
19 Mira St., Ekaterinburg 620002, Russian Federation

2I. 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

Two mutually complementary synthetic approaches 
towards 3‑substituted 3,4‑disubstituted and 

1‑(2‑pyridyl)‑substituted isoquinolines

Two mutually complementary synthetic approaches towards 3- and 3,4-disub-
stituted 1-(2-pyridyl) isoquinolines were studied. The aryne-based method was 
successfully used for the obtaining of the corresponding the 3-cyano-1-(2-pyri-
dyl)isoquinolines in one step / pot reaction, while it is unacceptable for the 
obtaining of other 1-(2-pyridyl)isoquinolines. The enamine-based approach was 
successfully applied for the synthesis of other 1-(2-pyridyl)isoquinolines, while 
it was unacceptable for the obtaining of 3-cyano-1-(2-pyridyl)isoquinolines.

Keywords: 1,2,4-triazines; arynes; enamines; isoqunolines; aza-Diels-Alder reaction; domino-
transfrormation.

Received: 08.09.2018. Accepted: 19.10.2018. Published: 31.10.2018.

© Nikonov I. L., Kopchuk D. S., Khasanov A. F., Krinochkin A. P., Starnovskaya E. S.,  
Shtaiz Ya. K., Savchuk M. I, Tanya O. S., Zyryanov G. V., Rusinov V. L., Chupakhin O. N., 2018

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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 pur-
poses can be obtained [1–3]. Recently, we 
have demonstrated the possibilities of their 
successful use in reactions with substituted 
1,2,4-triazines for obtaining both the ex-
pected aza-Diels-Alder reaction products, 
namely the corresponding isoquinolines, 
and the domino transformations, for ex-
ample, 10-(1H- 1,2,3-triazol-1-yl) pyrido 

[1,2-a] indoles. The direction of the reac-
tion depends on the nature of the 1,2,4-tri-
azines (or aryns) introduced into the com-
position of the substituents [4].

This article analyzes the two synthetic 
approaches we have developed for the syn-
thesis of 1- (2-pyridyl) isoquinolines with 
different substituents in the C3 and C4 po-
sitions, which are of interest, in particular, 
as ligands for transition metal cations [5], 
as well as from the point of view of creat-
ing OLED [6].

Nikonov I. L., Kopchuk D. S., Khasanov A. F., Krinochkin A. P., Starnovskaya E. S.,  
Shtaiz Ya. K., Savchuk M. I, Tanya O. S., Zyryanov G. V., Rusinov V. L., Chupakhin O. N.

Chimica Techno Acta. 2018. Vol. 5, No. 3. P. 150–152.
ISSN 2409–5613



151

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 cor-
responding 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 start-
ing compounds. The approach involves 
the preparation of 5,6,7,8-tetrahydroiso-
quinolines 4a as  a  result of  the reaction 
of aza-Diels-Alder (Boger) with enamine 
followed by oxidative aromatization of the 
isoquinoline system [8]. 1-Morpholinocy-
clohexene 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-carbo-
nitriles 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 prepa-
ration of tetrahydroisoquinolines 4b. The 
first step was performed by the same pro-
cedure as in the case of synthesis 4a, and 
afforded the compound 4b. However, sub-
sequent aromatization of tetrahydrocya-
noisoquinoline under various conditions, 
such as  boiling in  o-xylene or  4-chloro-
toluene 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 forma-
tion 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 mu-
tually complementary synthetic metho-
dologies can be used to synthesize 3-aryl, 
3,4-diaryl-, as well as 3-cyano-1-(2-pyri-
dyl)isoquinolines. Thus, in the case of R = 
CN (Scheme 1), the synthesis using aryne 
intermediates makes it possible to efficient-
ly obtain the corresponding isoquinolines 
3b, while the method based of the prepa-
ration tetrahydroisoquinolines 4b does 
not allow this because of the impossibility 
of subsequent aromatization by using the 
common methods. At the same time, in the 

Scheme 1. Reagents and conditions: i) Anthranilic acid, isoamylnitrile, toluene — 1,4-dioxane 
(4: 1), boiling, 1.5 h; ii) 1-morpholinocyclohexene, without solvent, 200 °C, 4 h; iii) DDQ, 

o-xylene, 143 °C, 10 h

N

N
NAr

R
N

N

Ar

R
N

N

Ar

R
N

R = H, Ph
R = CN

R = H, Ph
R = CN

i

ii
iii

N
N

N

N

Ar

R

R = H, Ph i

Ar = Ph, Tol, 4-BrC6H4

1a,b

2

3a,b

4a,b

(a) R = H, Ph
(b) R = CN  



152

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 interme-
diates, the reaction leads mainly to rear-
rangement products 2.

Experimental
NMR 1H and 13C spectra were recorded 

on the spectrometer “Bruker-Avance-400” 
(400 MHz), internal standard is SiMe4. 
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.

Acknowledgements
This work was supported by the Russian Science Foundation (Reference # 18-13-00365).

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