An efficient synthetic approach to 4′,5,5″-triaryl-2,2′:6′,2″-terpyridines

Article abstract of DOI:10.1016/j.tetlet.2015.12.006

An efficient synthetic approach is proposed to construct 4′,5,5″-triaryl-2,2′:6′,2″-terpyridines using two methods of pyridine ring construction, that is, the Weiss method and the '1,2,4-triazine' methodology. Due to the use of '1,2,4-triazine' methodolog

Full text of DOI:10.1016/j.tetlet.2015.12.006

Accepted Manuscript
An efficient synthetic approach to 4’,5,5’ ’-triaryl-2,2’:6’,2’ ’-terpyridines
Dmitry S. Kopchuk, Nikolay V. Chepchugov, Grigory A. Kim, Grigory V.
Zyryanov, Igor S. Kovalev, Vladimir L. Rusinov, Oleg N. Chupakhin
PII:
S0040-4039(15)30421-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.006
TETL 47053
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 August 2015
20 November 2015
1 December 2015
Please cite this article as: Kopchuk, D.S., Chepchugov, N.V., Kim, G.A., Zyryanov, G.V., Kovalev, I.S., Rusinov,
V.L., Chupakhin, O.N., An efficient synthetic approach to 4’,5,5’ ’-triaryl-2,2’:6’,2’ ’-terpyridines, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.006
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Graphical Abstract
An efficient synthetic approach to 4',5,5''-triaryl-
2,2':6',2''-terpyridines
Dmitry S. Kopchuk, Nikolay V. Chepchugov, Grigory A. Kim, Igor S. Kovalev, Grigory V. Zyryanov,
Vladimir L. Rusinov, Oleg N. Chupakhin

An efficient synthetic approach to 4',5,5''-triaryl-2,2':6',2''-terpyridines
Dmitry S. Kopchuk,a,b Nikolay V. Chepchugov,a Grigory A. Kim,a,b Grigory V. Zyryanov,a,b∗
Igor S. Kovalev,a Vladimir L. Rusinov,a,b Oleg N. Chupakhin,a,b
a Ural Federal University, 19, Mira St., 620002 Yekaterinburg, Russian Federation
b I. Ya, Postovsky Institute of Organic Synthesis of RAS (Ural Division), 22/20, S. Kovalevskoy/Akademicheskaya St., 620990 Yekaterinburg,
Russian Federation
Abstract
An efficient synthetic approach is proposed to construct 4',5,5''-triaryl-2,2':6',2''-
terpyridines using two methods of pyridine ring construction, i.e. the Weiss method and the
“1,2,4-triazine” methodology. Due to the use of “1,2,4-triazine” methodology in the last step,
aza-analogues of terpyridines as well as cycloalkane-annulated terpyridines have been
synthesized which are inaccessible by other reported methods. The presented approach involves
the use of readily available reagents and simple procedures.
Keywords: Weiss method, heterocyclization, 1,2,4-triazine, aza-Diels-Alder reaction, 2,2':6',2''-
terpyridine.
2,2':6',2''-Terpyridines represent an important class of heterocycles and are widely used as
ligands for metal complexes for various purposes.1 Thus, in materials science, 2,2':6',2''-
terpyridines are used as photosensitizers in Dye-Sensitized Solar Cells (DSSCs),2 and as
components for nonlinear optic (NLO) devices.3 In medicinal chemistry the antitumor activity of
some 2,2':6',2''-terpyridine complexes has been reported.4
In this communication we report an efficient synthetic approach for 4',5,5''-triaryl-
2,2':6',2''-terpyridines. Due to their broad range of activities, the synthesis of aryl-substituted
2,2':6',2''-terpyridine derivatives has gained special attention. Currently, there are a few literature
examples for the preparation of such scaffolds using 2-acetyl-5-bromopyridine as a starting
material.5 In this case, an aromatic substituent was introduced to position 5 by a cross coupling
reaction, followed by cyclization with the appropriate aromatic carbaldehyde according to the
Krönke method.
Herein, we report a novel approach for the synthesis of 2,2':6',2''-terpyridines by the
combination of two common methods for construction of the pyridine ring. Previously, we have
demonstrated two successful examples of using stepwise heterocyclization of a 1,2,4-triazine
∗ Corresponding author. Tel.: +7-343-375-4501; fax: +7-343-374-0458; e-mail: gvzyryanov@gmail.com

ring by the aza-Diels-Alder reaction to afford unsymmetrical functionalized aryl-2,2'-
bipyridines6 or 2,2':6',2''-terpyridines.7
Scheme 1. Reagents and conditions: i) КОН, EtOH-H2O (1:3), 0 °C, 15 min, then 20 °C,
overnight; ii) NaOH, MeOH, 5 °C, 1 h, then 20 °C, 40 h, 65%; iii) NH2OH•HCl, butan-2-ol, 100
°C, 20 h, 79%; iv) NaOH, KMnO4, pyridine-H2O (2:1), 20 °C, 2 h, then reflux, 10 min, 95%; v)
MeOH, SOCl2, 65 °C, 15 h, 100%; vi) NaBH4, EtOH, 78 °C, 2 h, 70%; vii) activated MnO2, 1,2-
dichloroethane, 50 °C, 10 h, 60%; viii) ethanol, 50 °C, 2 h, then AcOH, 118 °C, 2 min, 45%; ix)
neat, 200 °C, 3 h, then ethanol, 20 °C, 1 h, 70%.
The key-step of our method was to obtain 5,5'-diarylpyridines by means of a
heterocyclization reaction between isonitrosoacetophenone hydrazones and pyridine-2,6-
dicarboxaldehyde and subsequent aza-Diels-Alder reaction of the obtained 1,2,4-triazines with
various dienophiles.8 The main advantages of the “1,2,4-triazine” approach are: (a) the
possibility of obtaining various aza-analogues of terpyridines; (b) the possibility of further
functionalization at the C3 and C4 positions of the formed pyridine ring via variation of different
dienophiles;9 and (c) the easy introduction of various nucleophilic moieties at the C5 position of
the 1,2,4-triazine core by nucleophilic substitution of hydrogen with subsequent synthesis of
functionalized terpyridines, which are commonly inaccessible by other methods.10 It should also

be noted that the derivatives of 2,6-bis-(1,2,4-triazin-3-yl)-pyridines are of special interest as a
supramolecular extractants for various metal cations, including the actinide ions.11
The key starting reagent 4-arylpyridine-2,6-dicarbaldehyde could easily be obtained
from the corresponding pyridine-2,6-dicarboxylic acid or its ester. According to the literature, 4-
arylpyridine-2,6-dicarboxylic acid could be obtained by oxidative transformation of the furan
rings in 4-aryl-2,6-di(furan-2-yl)pyridine,12 or via different cross-coupling reactions of pyridine-
2,6-dicarboxylic acid or its ester substituted by chlorine,13 or, rarely, iodine14 atoms in the C4
position. In addition, the oxidation of methyl groups,15 or synthesis through the appropriately
functionalized dihydropyrone derivatives16 or pyrylium tetrafluoroborate15 are also reported.
In our approach the synthesis of 4-arylpyridine-2,6-dicarbaldehyde was carried out
starting from 4-aryl-2,6-di(furan-2-yl)pyridine, as this was the simplest approach which does not
require the use of any special conditions. The preparation of 4-aryl-2,6-di(furan-2-yl)pyridine
can easily be performed by the modified Weiss method12, 17 (Scheme 1).
Construction of the future central pyridine ring was performed according to the
presented method, starting from anisaldehyde 1 and 2-acetylfuran. During the first step, which
was performed according to reported methods,18 chalcone 2 was obtained by a Knoevenagel
reaction which was converted into compound 3 by a Michael addition.19 In the cases of products
2 and 3, the formation of a precipitate in the reaction substantially facilitates the process.
Furthermore, by using previously described conditions,12 2,6-difurylpyridine 4 was obtained by
the heterocyclisation reaction between 3 and hydroxylamine. It should be noted that, according
to our results, purification by sublimation under vacuum which was described in the reported
method12 was not necessary and compound 4 could be used for the next step without any
additional purification. Conversion of the furan rings to the carboxyl groups was performed
according to a modified procedure20 with the replacement of 1,4-dioxane by pyridine as a
solvent. The esterification reaction of pyridine-2,6-dicarboxylic acid 5, via the in situ formation
of the bis-chloroanhydride from the reaction with thionyl chloride followed by the addition of
methanol was unsuccessful. We observed the formation of by-products, which was probably due
to acylation of the 4-methoxyphenyl substituent. However, heating compound 5 in hydrogen
chloride saturated methanol yielded the target ester 6 with sufficient purity and in quantitative
yield. Finally, the reduction of ester 6 with sodium borohydride and subsequent oxidation of 2,6-
dihydroxymethylpyridine 7 using activated MnO2 afforded the desired pyridine-2,6-
dicarbaldehyde 8. Heterocyclization of the 1,2,4-triazine rings was performed according to a
modified procedure.8 Finally, the aza-Diels-Alder reaction between 1,2,4-triazine 9 and 1-
morpholinocyclopentene under neat conditions at 200 °C afforded the cyclopentene-annulated

2,2':6',2''–terpyridine 10. It should be noted that these types of cycloalkane-annulated pyridine
ligands are of practical interest, particularly due to their high solubility in non-polar solvents.21
1
The structures of the compounds 9 and 10 were in accordance with the H and 13C
NMR, MS-ESI and elemental analysis data. In particular, in the 1H NMR spectrum of bistriazine
9 the characteristic resonance of protons at the C5 position of the 1,2,4-triazine fragment was
observed as a two proton singlet at 9.60 ppm along with signals for the resonances of the
aromatic substituent protons as multiplets between 7.00-7.60 ppm and signals for the resonance
of protons at positions C3 and C5 of the pyridine ring as one proton singlets at 8.92 ppm and
1
9.60 ppm. In the H NMR spectrum of cyclopentene-annulated terpyridine 10 the resonance
signals of the cyclopentene protons in the aliphatic region appeared along with a downfield shift
of signals for the resonance of protons at positions C3 and C5 of the central pyridine ring and the
cyclopenta[c]pyridine moiety as compared with bis-1,2,4-triazine 9.
In order to estimate the photophysical properties of terpyridine 10 we also prepared
terpyridine 11, which does not have an aryl substituent on the central pyridine ring.8 For this
purpose the modified solvent-free method was applied to the reaction starting from 2,6-bis-
(1,2,4-triazin-3-yl)-pyridine 128 (Scheme 2).
Scheme 2. Synthesis of terpyridine 11. Reagents and conditions: i) 1-morpholinocyclopentene,
neat, 200 °C, 3 h, 65%.
Table 1 demonstrates the photophysical data for compound 10 (entry 1), compound 11
(entry 2) and selected terpyridines, which were previously reported in the literature, for instance
4-methoxy-2,6-dimethylphenyl(manisyl)-substituted terpyridines22 (entry 3-4) and 6,6’’-dicyano-
diaryl-substituted terpyridines23 (entries 5-7). In addition, the photophysical data for the
phenanthrene-based analogue 1322 of terpyridine was added.
Table 1. Photophysical properties of aryl-substituted terpyridines and their analogues
b
Entry R1
R2
R3
n
Solvent λabsa (nm) λem
Ф
(%)

(nm)
1
2
4-MeOPh
H
H
H
Ph
Ph
3
3
CH3CN 215, 245,
313, 328sh
4.4c
533
CH3CN 247, 306, 389
331
56.6c
3
4
5
6
7
8
H
H
H
H
H
H
Manisyl
H
0
0
0
0
0
CH3CN 286
CH3CN 284
408
412
355
363
402
443
85d
8d
Manisyl
CN
Ph
EtOH
EtOH
EtOH
302
305
313
40e
50e
60e
44c
CN
Tol
CN
4-MeOPh
CH3CN 296
13
aAbsorbtion maxima at room temperature; luminescence maxima at room temperature;
b
c
quantum yields measured in CH3CN using quinine sulfate as a standard;24d literature data;22e
literature data23
Based on the photophysical data, terpyridine 10 demonstrated the most pronounced red-
shift (∆λem = 144 nm) in the emission spectra (Table 1, entry 1) compared to non-aryl-substituted
terpyridine 11 (Table 1, entry 2) and other literature reported terpyridines. The emission spectra
of terpyridines 10-11 are presented in Figure 1. Manisyl-substituted terpyridines demonstrate
less pronounced red-shifts in the emission spectra compared to compound 11 (Table 1, entries 3-
4). The same observation can be made for the cyano-substituted terpyridines: in the case of bis-
(4-manysil)-substituted terpyridine the red-shift of the emission maxima to 402 nm (Table 1,
entry 7) has been observed. Only in one case was a significant red-shift of the emission maxima
to 443 nm (∆λem = 54 nm) achieved using compound 13 (Table 1, entry 8) due to the
replacement of the terpyridine core by a more conjugated pyridyl-substituted 1,10-phenanthrene
core.

400
350
300
250
200
150
100
50
0
400
450
500
550
600
650
700
750
800
Wavelength, nm
Fig. 1. Luminescence spectra of terpyridines 10 (solid line) and 11 (dashed line) in MeCN at
room temperature
Unfortunately, the fluorescence quantum yield for compound 10 was relatively low (i.e.
4.4%) compared to 11 (56.6%). This may be attributed to a greater contribution of n-π* excited
states in fluorescence.25c In order to investigate the influence of the nature of the aryl substituents
on the photophysical properties of 4,4'',5'-terpyridines more-detailed studies are needed. The
reported method for the synthesis of 4,4'',5'-terpyridines opens many possibilities for these
studies as further variation of substituents on the central pyridine core are possible. It is worth
mentioning that successful attempts have previously been made aiming to tune the photophysical
properties of oligopyridines by changing the type of aromatic substituents on the pyridine core,
for instance in a series of 2,2'-bipyridines25 or pyridyl-monoazatriphenylenes.26
In summary, an effective method was developed for the preparation of 4',5,5''-triaryl-
2,2':6',2''-terpyridines by sequentially using two different methods for construction of the
pyridine rings, such as the Weiss method and “1,2,4-triazine” method. The present approach
involves only the use of readily available reagents and simple procedures. In addition, the
application of the 1,2,4-triazine methodology provides a simple route towards aza-analogues of
terpyridines, which have a particular interest as metal cation chelates, as well as cycloalkene-
annulated terpyridines, which are inaccessible using other synthetic approaches. The
photophysical properties of 4',5,5''-triaryl-2,2':6',2''-terpyridine have also been studied and
compared to the photophysical properties of 2,2':6',2''-terpyridines which are unsubstituted at the
4' position. It has also been demonstrated that a large red-shift of the emission maximum caused

by the introduction of an aromatic substituent into the central pyridine ring of the 2,2':6',2''-
terpyridine system is possible.
Acknowledgements
This work was supported by Russian Science Foundation (Ref. # 15-13-10033)
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Highlights
Highlights
An efficient synthetic approach to 4',5,5' '- triaryl-2,2': 6 ', 2' '- terpyridines has been developed.
Readily available reagents and simple procedures have been used.
Photophysical properties of resulted 4',5,5' '- triaryl-2,2': 6 ', 2' '- terpyridines have improved.
Further modification is possible through the aromatic moiety attached to a central pyridine ring.
Therefore, we believe that our work will attract the interest of the readers of Tetrahedron Letters.