A rational protocol for the synthesis of 1-(2-pyridyl)isoquinolines

Article abstract of DOI:10.1016/j.mencom.2013.05.007

Aza-Diels-Alder reaction between 3-(2-pyridyl)-1,2,4-triazines and 1-morpholinocyclohexene followed by aromatization of the cyclohexene moiety affords 1-(2-pyridyl)isoquinolines. Crystal structures of two tetrahydroisoquinolines were confirmed by X-ray diffraction analysis.

Full text of DOI:10.1016/j.mencom.2013.05.007

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 142–144
A rational protocol for the synthesis of 1-(2-pyridyl)isoquinolines
Dmitry S. Kopchuk,*a,b Igor S. Kovalev,a Albert F. Khasanov,a Grigory V. Zyryanov,a,b
Pavel A. Slepukhin,b Vladimir L. Rusinova,b and Oleg N. Chupakhina,b
a Department of Organic Chemistry, Ural Federal University, 620002 Ekaterinburg, Russian Federation
b I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation. Fax: +7 343 374 1189; e-mail: dkopchuk@mail.ru
DOI: 10.1016/j.mencom.2013.05.007
Aza-Diels–Alder reaction between 3-(2-pyridyl)-1,2,4-triazines and 1-morpholinocyclohexene followed by aromatization of the
cyclohexene moiety affords 1-(2-pyridyl)isoquinolines. Crystal structures of two tetrahydroisoquinolines were confirmed by X-ray
diffraction analysis.
Isoquinolines and tetrahydroisoquinolines are important class of
heterocycles due to their presence in a wide range of naturally
R1
R2
R1
R2
R1
R2
N
occurring compounds. Isoquinoline derivatives exhibit various
biological activities,1 including anti-HIV,2 antimalarial,3 ion-
channel blocking activity,4 act as dopamine agonists,5 and are
present in some alkaloids.6 Pyridyl-substituted isoquinolines
are of wide use as ligands for copper,7 as chiral catalysts8 and
phosphorescent emitters for OLEDs.9 Traditional synthetic routes
to isoquinolines are the Bischler–Napieralski, Pomeranz–Fritsch
and Pictet–Spengler reactions, which involve the intramolecular
cyclization under the drastic conditions.10 Pyridyl-substituted
isoquinolines can also be accessed by cross-coupling reactions,11
N
ii
i
N
N
N
N
N
N
3a–e
2a–e
1a–e
R1
R2
Yield of 2 (%) Yield of 1 (%)
a
b
c
d
e
p-Tol
4-ClC6H4
4-BrC6H4
H
H
H
H
Ph
Ph
40
44
38
37
54
63
67
59
51
68
r
eactions mediated by organolithium compounds,12 as well as som
e
Ph
heterocyclization reactions.13 In addition, some new synthetic
approaches to isoquinolines appeared in a literature, especially
due to the development of metal-catalyzed organic synthesis14 as
well as modern aryne chemistry.15 Thus, an efficient synthesis of
isoquinolines from alkynes and iododiimines and ketimines,16 as
well as palladium-catalyzed aryne annulation with ortho-halo-
aldimines affording isoquinolines17 were reported. Recently18
we described the synthesis of pyridyl-substituted isoquinolines
using non-catalyzed cycloaddition of substituted 1,2,4-triazines
and arynes generated in situ.
Herein we propose a rational protocol for the synthesis of
pyridyl-substituted isoquinolines by the inverse demand Diels–
Alder reaction of 1,2,4-triazines (Scheme 1). The first precedent
of such a reaction was reported19 in 1969 and nowadays this
approach is of high demand.20 However, the inverse demand
Diels–Alder reactions have never been used for the preparation
of pyridyl-substituted isoquinolines.
Scheme 1 Reagents and conditions: i, 1-morpholinocyclohexene (neat),
200°C, 4 h; ii, DDQ, o-xylene, 143°C, 10 h.
corresponding tetrahydroisoquinolines in yields less than 25%.
The solvent-free procedure24 at the same ratio of reactants (ca.
1:5) and the temperature of 195–200°C was significantly more
effective: the target tetrahydroisoquinolines 2 were isolated in
37–54% yields.† Note that all the products were simply purified
by recrystallization and in most cases no column chromatography
was needed.‡
Structures of products 2 were confirmed by spectral data. In
addition, the crystal structures of compounds 2c and 2e were
proved by X-ray diffraction analysis (Figure 1).§
The subsequent aromatization of products 2, for instance by
the solvent-free heating over 10% Pd on carbon25 afforded iso-
quinolines 1 only in 10–15% yield, and a significant amount of
oily by-products was detected in the reaction mixture. The proce-
dure using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
Starting 1,2,4-triazines 3 were synthesized by described21 cyclo-
condensation between the corresponding amidrazones and dicar-
bonylcompoundsorbetweenisonitrosoacetophenonehydrazones
and pyridine-2-carboxaldehyde. Our investigations began with
examining the reaction conditions for preparing tetrahydroiso-
quinolines. According to the published data, various dienes can
be efficiently applied for obtaining pyridine derivatives from
1,2,4-triazines. In most cases 1,2,4-triazines and enamines of
pyrrolidine22 were utilized to prepare the corresponding pyrido-
cyclopentenes. Only in a very few cases 1-morpholinocyclo-
hexene was used for similar purposes.23
†
Preparation of bipyridines 2 (general procedure). A mixture of the
corresponding triazine 3 (2 mmol) and 1-morpholinocyclohexene (1.68 ml,
10 mmol) was stirred at 200°C for 2 h under argon. Then the additional
portion of 1-morpholinocyclohexene (0.84 ml, 5 mmol) was added and
the mixture was stirred for additional 2 h. The resulting solution was
cooled to room temperature. Acetonitrile (20 ml) was added and the reac-
tion mixture was kept at –18°C for 15 h. The fine crystalline precipitate
formed was filtered off, washed with acetonitrile and dried. Analytically
pure sample was obtained by recrystallization from acetonitrile.
For characteristics of compounds 2a–e, see Online Supplementary
Materials.
We found that in case of enamine as the dienophile the product
yield depended on the reactant ratio and the reaction temperature.
Thus, refluxing of corresponding 1,2,4-triazines and 1 to 5 equiv.
of 1-morpholinocyclohexene in aromatic solvents afforded the
‡
In case of bipyridine 2d column chromatography (CHCl3, Rf = 0.2) was
used to purify the product.
© 2013 Mendeleev Communications. All rights reserved.
– 142 –

Mendeleev Commun., 2013, 23, 142–144
the Russian Foundation for Basic Research (grant no. 12-03-31726)
and the Council for grants of the President of the Russian Federa-
tion (grant no. MK-1511.2013.3).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.05.007.
2c
2e
References
Figure 1 Molecular structures of bipyridines 2c and 2e. Hydrogen atoms
in 2e are omitted for clarity.
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§
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–
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¶
Preparation of isoquinolines 1 (general procedure). A mixture of the
corresponding bipyridine 2 (0.5 mmol), DDQ (114 mg, 0.5 mmol) and
o-xylene (40 ml) was refluxed for 3 h. Additional portion of DDQ (114 mg,
0.5 mmol) was added and the reaction mixture was refluxed for additional
3 h. Then the final portion of DDQ (114 mg, 0.5 mmol) was added and
the resulting mixture was refluxed for 4 h. The solvent was removed under
reduced pressure, the residue was purified by column chromatography
(neutral Al2O3, chloroform).
For characteristics of compounds 1a–e, see Online Supplementary
Materials.
– 143 –

Mendeleev Commun., 2013, 23, 142–144
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Received: 5th February 2013; Com. 13/4063
– 144 –